The Peter Attia Drive - #62 - Keith Flaherty, M.D.: Deep dive into cancer—History of oncology, novel approaches to treatment, and the exciting and hopeful future

Episode Date: July 15, 2019

In this episode, Keith Flaherty, director of clinical research and targeted cancer therapy at Massachusetts General Hospital, shares his vast wealth of knowledge in cancer starting with the history of treatment from chemotherapy to radiation to surgical therapy and where those methodologies seemed to have leveled off. He also walks us through the timeline of advancements (and lack there of) from when the War on Cancer was declared in the 1970s, through the sequencing of the entire human genome, and all the way to today. Keith dives into the topic of immunotherapy, probably the most exciting recent development in cancer therapy, and also provides us a rundown of his notion of a different approach to cancer that attacks all the essential pillars of cancer growth and survival. Finally, we talk a little bit about liquid biopsies, we discuss the roles of CRISPR and other potentially over-hyped therapies with respect to cancer. We also touch on stem cell therapy a bit, as well as some other common cancer-related questions such as the role of vitamin D and sun exposure in melanoma, and much more. We discuss: Growing up around medicine, and finding a career that you love [7:30]; Medicine as a career, limitations of the med school teaching approach, and the dynamic and accelerating field of medicine and technology [16:30]; Explaining chemotherapy, radiation, and how a cancer develops [23:45]; Surgical oncology, cure rate of solid tumors, and survival rate after tumor removal  [33:15]; 25 years after the War on Cancer is declared, gene sequencing, and why Keith’s was fascinated by the HIV case study [37:15]; Cancer immunotherapy: History, how it works, and why some cancers respond and others don’t [46:00]; MHC complexes, and cancer cloaking mechanisms [56:00]; Comparative biology of cancer: Why some cancer can evade immune detection better than others [1:03:00]; What we learned from the Cancer Genome Atlas Project [1:07:00]; Defining targeted therapy, HER2 breast cancer, chronic leukemia, and the translocation of chromosomes [1:12:00]; Tumor protein P53, the most famous tumor suppressor gene and its ubiquity in cancer [1:17:45]; Activated oncogenes, the RAS pathway, PI3 kinase, RAF gene, and Keith’s “aha moment” [1:24:15]; Advice for starting your career as a scientist/clinician [1:37:00]; Fusion-driven cancers, targeted therapy, and the Bcr-Abl/chronic myelogenous leukemia case study [1:39:45]; Targeted therapy for fusion-driven solid tumors, adjuvant systemic therapy, and the HER2 breast cancer example [1:53:00]; Advancing melanoma treatment, survival, and cure rates with BRAF-MEK combo therapy [1:59:15]; The fundamental pillars of cancer growth and survival, and the toolkit we need to attack cancer from all angles [2:02:40]; Peter’s clinical framework for thinking about cancer and how Keith might improve it, and how the biotech environment is hampering our ability to put together novel cancer treatments [2:05:00]; How useful is CRISPR in terms of tumor suppressing? [2:16:15]; Liquid biopsies as a therapeutic monitoring tool [2:18:00]; Stem cell therapy: The efficacy and potential risks [2:25:15]; Aging and cancer: Is cancer inevitable? [2:28:45]; Vitamin D supplements, sun exposure, melanoma, and exercise [2:32:30]; How and why Keith has straddled the line between science/research and industry/drug companies, and the importance of getting more voices of practitioners at the table [2:42:00]; and More. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful, top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterottiamd.com. Hey everybody, welcome to this week's episode of The Drive. I'd like to take a couple of minutes

to talk about why we don't run ads on this podcast and why instead we've chosen to rely entirely on listener support. If you're listening to this, you probably already know, but the two things I care most about professionally are how to live longer and how to live better. I have a complete fascination and obsession with this topic. I practice it professionally, and I've seen firsthand how access to information is basically all people need to make better decisions and improve the quality of their lives. Curating and sharing this knowledge is not easy, and even before starting the podcast, that became clear to me. The sheer volume of material published in this space is overwhelming. I'm fortunate to have a great team

that helps me continue learning and sharing this information with you. To take one example, our show notes are in a league of their own. In fact, we now have a full-time person that is dedicated to producing those, and the feedback has mirrored this. So all of this raises a natural question. How will we continue to fund the work necessary to support this? As you probably know, the tried and true way to do this is to sell ads. But after a lot of contemplation, that model just doesn't feel right to me for a few reasons. Now, the first and most important of these is trust. I'm not sure how you can trust me if I'm telling you about something when you know I'm being paid by the company that makes it, to tell you about it. Another reason selling ads doesn't feel right to me is because I just know myself. I have a really hard time advocating for something that I'm not absolutely nuts for.

So if I don't feel that way about something, I don't know how I can talk about it enthusiastically. So instead of selling ads, I've chosen to do what a handful of others have proved can work over time, and that is to create a subscriber support model for my audience. This keeps my relationship with you both simple and honest. If you value what I'm doing, you can become a member and support us at whatever level works for you. In exchange, you'll get the benefits above and beyond what's available for free. It's that simple. It's my goal to ensure that no matter what level you choose to support us at, you will get back more than you give. So for example, members will receive full access to

the exclusive show notes, including other things that we plan to build upon, such as the downloadable transcripts for each episode. These are useful beyond just the podcast, especially given the technical nature of many of our shows. Members also get exclusive access to listen to and participate in the regular Ask Me Anything episodes. That means asking questions directly into the AMA portal and also getting to hear these podcasts when they come out. Lastly, and this is something I'm really excited about, I want my supporters to get the best deals possible on the products that I love. And as I said, we're not taking ad dollars from

anyone, but instead what I'd like to do is work with companies who make the products that I already love and would already talk about for free and have them pass savings on to you. Again, the podcast will remain free to all, but my hope is that many of you will find enough value in one, the podcast itself, and two, the additional content exclusive for members to support us at a level that makes sense for you. I want to thank you for taking a moment to listen to this. If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription. My guest this week is Dr. Keith Flaherty. Keith is a physician scientist at Massachusetts General Hospital in Boston, where he's the director of clinical research as well as targeted therapies. His research focuses on the understanding of targeted

therapies in cancer. And if that term is a bit nebulous to you, don't worry about it. We define it quite clearly. And he focuses on the development of responses and predictive biomarkers to define the mechanisms of action and resistance of novel therapies. He's researched a lot of stuff in immunotherapy. So this is really the first podcast that I discuss immunotherapy in, which for me is super exciting because I've been looking forward to discussing this topic for quite some time. And you'll see why when we get into it, because immunobased therapies are basically the most exciting recent development in cancer therapy. And we talk quite a bit about these checkpoint inhibitors for

which actually the Nobel prize in medicine and physiology was awarded last year. He's been a PI in a too numerous account, first in human clinical trials using novel therapies. What else can I say? He's a professor of medicine at Harvard Medical School and serves as editor in chief of the journal Clinical Cancer Research. Overall, Keith is really a wealth of knowledge in cancer. We talk about a bunch of stuff now. Honestly, the first 20 minutes, we're just talking general life medicine. We don't even touch on cancer. So if you're short on time and you really just want to get into the stuff on cancer, definitely jump ahead to 20 minutes into this stuff. We talk quite a bit about the history of chemotherapy, what its successes were, why they asymptoted, same with radiation therapy, surgical therapy, and ultimately what took place and what didn't take place,

maybe more to the point, in the period of time between when the war on cancer was declared in 1974 and the sequencing of the entire human genome about 25 years later. And then we talk about what took place in the two decades since that time. And you'll see that, well, at least even for me, I think you'll tell, I was actually learning quite a lot here vis-a-vis how some of those changes took place. And again, for that reason, this was a highly enjoyable experience, even if not one person listens to this podcast, I got a ton out of it. We basically got into this notion of what's a different approach to cancer. And again, clinically, I found this very helpful because this is a problem I think a lot about. So I do

think people will enjoy this. We talk a little bit about liquid biopsies, even touch on roles of potentially CRISPR and overhyped with respect to cancer therapies, potentially even at the end, talk about stem cell therapy, vitamin D, melanoma, sun exposure, the list goes on. This is a pretty long episode. So hopefully we talk slow enough that you can listen to it at a slightly higher speed. And the show notes as always will contain a ton of information, not just links to the studies we talk about, but a lot of the semantics. I wouldn't be discouraged if you find this topic and particularly this episode to be somewhat challenging based on how technical it gets at times. I think we both do a pretty good job of remembering that we're not just talking with each other. And I try to ask questions to bring us back 30,000 feet and focus on the big stuff.

But in many ways, I think this will be probably the deepest podcast I've done to date on cancer, though certainly not the last. So without further delay, please enjoy my conversation with Dr. Keith Flaherty. Keith, thank you so much for letting me intrude in the middle of your living room on a rainy Monday afternoon. My pleasure, Peter. Is this normal Boston April weather? This is the wet season, mud season as they call it, but it's a welcome break from winter. Hasn't been a particularly harsh one, but yeah, it's a good, good transition time. It was brown last week, so everything's just finally waking up. Now you've pretty much spent your whole life from basically Connecticut to, or actually Connecticut, south of Boston, right? So,

so it's sort of basically Boston to Baltimore has been most of your life. That's right. Born and raised in Baltimore, broke away to boarding school in Massachusetts for four years, Connecticut for college, four years, then back to Baltimore, four years of medical school, Boston for the first time, three years of residency, and then Philadelphia for nine years, which was both medical oncology fellowship and my first faculty stint. And now 10 years ago, I moved back up to Boston to Mass General. So this fall will be 10 years. But as you say, Northeast corridor through and through. Yeah. Well, you get your seasons, right? Yeah. That's always my defense of the Northeast to Californians is I need the seasons. And certainly during my educational years, I always thought if I had San Francisco, LA,

or God forbid, San Diego weather, I'm not sure I really would have been able to keep my nose to the grindstone. Seasons are good to kind of force you inside and take your breaks when you need them. Well, I think there's something else about it that I sort of lament. Both my wife grew up in Baltimore, I grew up in Toronto, and there is an intestinal fortitude that comes from being in a climate that is not particularly hospitable. You get a little tougher as a kid, I think, when you have to pay attention. Like if you forget your gloves, you're hosed. Yeah, you're going to pay for it. I suppose that's true. I think

resilience comes from a few parts of one's upbringing, but the climate is probably, you're right. It's at least a bias of mine that it's a good thing to have. Even as the years keep passing and I think about, well, where would I want to spend the next 10 years, 20 years beyond? I love it up here. I mean, for me, it's really, it gets just brutal enough in the winter, but not Canadian brutal. Although Boston is its own little, Boston and Toronto are not that different. Oh, okay. Yeah. Montreal might be worse. Yeah. I just have more figuring latitude drives harshness of winter. I have more respect for Canadian

winters, but maybe it isn't that different. I feel like, again, just gets harsh enough. And then in the summertime, get the payoff for the flip side, which is just so pleasant, but not like Baltimore burdensome in terms of the heat and humidity. So you're kind of one of these guys who was exposed to medicine throughout, right? But I know your father is a physician. Your mother was as well, right? Yeah, that's right. My father was an academic cardiologist for 25 years and then almost an equal stint in industry, pharma and biotech.

And my mom was an academic psychiatrist, actually really still is at the age of now 70, will be 76 end of this month. Very different career in psychiatry versus cardiology, but an academic career nonetheless. So a bit of research, a lot of teaching, mentoring, and that bit continues. She has incredible stamina for staying connected with her field. She's retired from patient care a good long time ago, but couldn't give up the rest. And so continues to haul herself off to conferences and oral examinations that are still required for psychiatric boarding and so on. So kind of an inspiration in terms of longevity in the field.

You knew pretty early that you wanted to go into medicine, or was that not even clear when you went off to college? Yeah, no, it wasn't clear to me at all. I mean, I honestly would have to admit that I didn't really understand how my parents' worlds turned. They were perfectly transparent and happy to talk about their careers. I just didn't know to ask the questions. The two older brothers who then and now had no interest in science or medicine, I guess all that I could say from a young age, maybe by the time I was in boarding school and going to college, was that some way, somehow I wanted to help people.

This is a phrase I recall saying, but I had no idea what that might mean and what the different versions of it were. As years passed, I got more and more of the sense that a lot of how the world turned was kind of transactional business transactions, I suppose, people making careers on some version of transaction. I had this aversion, I was developing this aversion to that idea that I didn't want to be involved in what I broadly construed to be business. Now we'll come back to this later. I was about to say the irony, but okay. Absolutely. I'm laying that right out, right out there for you. There's so many ways in which I turned on that. There's a, I mean, in a good way I've turned on those initial principles, but

yeah, any case, I thought this idea that I needed to find a path where I felt like I was very directly helping people was going to be the most sort of satisfying career and something that would get me out of bed in the morning without having to really try. That part, I'd say, really did work out. So I think that's probably the one piece that I think I did get from my parents. So I didn't know exactly what they did when they got to the hospital. But you had some sense that it involved people and they were in a probably a more direct way of helping them. I mean, you could argue most people are helping people in some way,

but you knew that there was fewer degrees of separation. That's right. And then that final point that they were super motivated by their careers. It was never a complaint. There was one thing about their marriage. They would talk about just inside baseball of division, department, hospital level politics and issues that were kind of headwind for them. And you hear them talk about their real mechanistic elements of their careers. And it just was never a complaint about it. They were very kind of focused on results and group dynamic and so on. But I guess my point is that you never had a notion that they did not

love what they did. And end of every vacation, end of every weekend, I mean, they were just like hard charging back at work. My parents, because they were both building academic careers when we were young, they were oftentimes alternating evening duty. One of them, even for a whole week at a time, tied up either on service or something that was keeping them in the hospital. So watching that conviction and how much they just loved doing that thing that I didn't understand, that was probably the very nebulous notion that I kept with me. So that as I kept kind of crossing off like vast segments of American economy had to offer in terms of careers, medicine's kind of the thing that remained. Yeah. It's an interesting point you raise about the fine line for parents in terms of the example setting versus the time

there. I mean, both are really important, right? I mean, I know this now I have kids met your daughter earlier. There's in some ways, no substitute for this term quality time sort of always struck me as a little bit of a hoity toity term. I mean, there's time and there's no time, right? But call it quality time. And there's no substitute for that, but there's something to be said when a child sees their mom or dad feeling incredibly passionate about what they're doing and how without saying a word about that, it sets an example. Yeah. I hear my daughters talk about this in relation to my wife. She's an internist at Mass General and she's part-time, but because of EPIC, the electronic medical record, she's full-time and then some because for every minute

she takes care of a patient directly, she's taking care of their medical record for three to five minutes easily. That sounds like an excellent ratio. Yeah. And of course the kids see that side, right? Because they're not with her in the hospital, but they see the constant overflow. They know what she does in principle and internists, I guess, maps to a pediatrician. They have direct experience with that, but they watch her pour herself into the indirect care of patients through the electronic micro record and constantly reflect that she's the hardest working person they know. And that example, like this, that kind of willingness to like give, give, give outside of one's personal time, family time, it's related to what I was trying to put words to, but this very nebulous notion of what it is that qualified as a satisfying career.

I've spent my adult life, particularly raising kids, making this comment that in my imagination, a number that I often come back to is like 95% of people don't like what they do. And they're just holding their breath trying to get to the weekend or vacations. And maybe I'm vastly off base, but I guess I'm partly using a high number like that because I just feel incredibly fortunate to have been brought up in a household and educational environment serially that my parents made available to me that allowed me to be in that, what I think is a relatively small group where I just always loved what I did and just felt like I had absolute choice and could engineer my schedule in every respect in a totally suicidal,

not respectful of balance way. I mean. I just developed a career that was ridiculously off the rails in terms of being overcommitted and trying to juggle way too many things in some respects. For me, I would defend it also and say it was exactly the optimal amount of chaos that one needs to really feel like you're kind of pushing on all fronts simultaneously. But how do you both find the outlet and define the scope of a career that allows you to do that? Man, what a challenge. And what a different challenge I think that our children will have versus what it was like to try to build a career, in this case in medicine, starting decades ago versus what they're looking at. And medicine still may be one of the slightly

easier places to do it because the path to quote unquote academic success, non-academic clinical success, it's still relatively unperturbed from so many other paths, right? Outside of medicine, or is that not even true anymore? I don't see it that way, but I'd be interested in your perspective as a surgeon, because I think maybe we have a different angle on that being in medicine versus surgery, which obviously culturally we've always had some real differences, not just culturally, sort of skill sets. So the thing that I've been deliberating on, let's say this, I've had a 20 year oncology career, almost 20 years, a few months away from that. And so I divide my career up into these two decades and I've watched technology advance and the field-wide body of knowledge accelerate in a 2000 to 2010 interval and then these past 10 years. And this is true in so many areas of

technology advance, but in biomedical research and in cancer, which is my only area of any expertise, I thought 2000, 2010 was mind-blowing. And I thought we were going to spend time catching up with the mind-blowing advances. That was my talking point coming into the field in 2000, that I thought, we've got this huge wave of molecular insights, mostly genetic insights in terms of cancer, that had built up, but hadn't been transformed into medicine. That was my unbelievably naive, simple-minded pitch as I was entering the field, and I said, I want to make myself useful in that translation of science to medicine. Anyway, 2000 to 2010, then you could say we're the first chapter of translating

molecular insights into medicine and oncology. Well, 2010 to 2020 makes that first decade look unbelievably slow. And where it was every two years, there was maybe a monumental event, whereas now it's like six at a time. So that's in terms of like crossing the finish line. But in terms of data generation, ability to produce high dimensional data, analyze it, try to make sense of it, raise hypotheses, test hypotheses. Yeah, the cycle time is changing a lot. And the constituents that we now need to interact with are totally different. But the point I'm coming to, to answer your question is, I see medicine now as this terrifying arena in which to try to assemble

a multi-decade long career. Like how do you keep yourself relevant in a, let's say 40 year arc? Here I am at 20 years and feel like I'm an absolute dinosaur. Mentoring is the thing that I think I can still do with some relevance to the younger generation. And in mentoring them, with some relevance to the younger generation. And in mentoring them, I tell them, look, you need to learn how to talk to a bioinformatician, computational biologist. I couldn't have even imagined 10 years ago that I'd be telling my mentees that,

much less that I would have this notion that I need to understand the world from that degree of mathematical modeling complexity. But it's having now mentees who were in computational biology myself, I've come to, but it's having now mentees who were in computational biology myself, I've come to realize that it's, I didn't have the skillset at the dawn of my career. Is it possible for people, broadly speaking, to actually retrain themselves and grow a new lobe of their brain? It's possible, but it's going to force a totally different paradigm in terms of

how one thinks about taking breaks, taking sabbaticals, gaining that knowledge base. So I was actually thinking of something different, but what you're bringing up is more interesting. So I want to double click on that before we jump into the meat of what we're going to talk about. Based on the way you're describing it, I would say doctors coming out of training are hosed because medical school, and I'm going to really make a lot of enemies by saying this, but I guess it's my podcast. I'm allowed to say this. I think medical school might be one of the most anti-intellectual forms of higher education that exists. I mean, when you contrast it with even the experience that many people have in college, where you really get to think creatively, you really get to problem solve. You really get to explore the limits of what is known and what is

not known and ask questions. Not having gone to law school, but my brother did. I got to see my brother do that in law school. Having more friends than I can count who did PhDs in everything from the humanities to the sciences, they got to do that. Well, I went to a good medical school, but that's not the way my education was. And I'm not sure it's that much more like it today. In other words, I'm not sure medical school teaches you how to be a thinker or a problem solver or even, and maybe again, I hope I'm wrong, but if you don't learn how to learn and God forbid the people who go into medical school as pre-meds. So then they've

missed out on at least taking an engineering degree or taking a humanities degree where you would have got some of that stuff. So, so yeah, then I think you're in real trouble. I totally agree with you. And the word that you didn't use that I'll use is investigation. That's not taught. And at best it's taught in a retrospective field wide introspective way. And by that, I mean like diagnostics. I mean, thinking about how to diagnose illness in medical school is beginnings of teaching that concept. I actually tell people the one type of statistics that physicians get very well trained in without explicitly being told what they're doing is Bayesian statistic, because that really is clinical medicine. Clinical medicine is

pure Bayesian statistics. It is learning how to update your pre-test probability with new information over and over again. And the reality of it is that doctors get very good at that. It's never codified and formalized such that they understand that that's actually what's being taught. Yeah. Although contaminated by bias as in recency bias, right? So this is, there's a huge issue in the practice of medicine that you're so clouded by the last few outcomes. Your participability is not as accurate as it could be if you were able to eliminate it. Going back to that point that medical school, it teaches information as fact. It teaches the known. That known-unknown divide is exactly, it's my pitch in academic medicine, at least talking to people about cancer as a career.

I tell them, look, it's so simple to find the boundary between what's known and not known. There's so much out there we don't know. And in any area of trying to understand physiology, pathophysiology in the mode of cancer, you will so quickly get to that frontier. And then how do you operate in that frontier? Once you're there, how do you help the patient in front of you, the next wave of patients that are coming in the not too distant future, and then like a full generation out? How do you help across that gradient? Well, investigation is the only way you can pose yourself as being helpful. And that, I didn't get that in medical school, sadly, even though I was at a fantastic environment for learning the archival version of medicine.

That's a great way to distinguish, right? I mean, you go to a place like Hopkins, you're going to get the best archival education imaginable. You're walking through the halls where the actual profession came to North America. And I actually, it was one of the things I cherished when I was there and the few books I brought with me out of medical school, surrounding myself with books that are not medicine as a general sport, were the history of medicine. I mean, Osler particularly, I thought was absolutely an Aristotelian figure. So I thought those are the roots and we have to figure out how to reimagine ourselves like those great builders of the medical discipline. So it was very

retrospective and it wasn't really honoring the notion that everybody in the field, particularly these big academic centers that are given tons of resources to investigate, can and should see themselves as being absolutely on the frontier. It's a more dynamic frontier now than ever before, mostly because the sensing technology to be able to actually understand what's wrong in the system. And when you perturb the system with the therapy, how the system responds, cancer is such a great example of this. Our sensing technologies have just gone berserk in terms of the acceleration. So there's just so much more that one can learn. But again, this is the concept that only, even in my oncology training, I didn't get that. And my oncology training was the same notion of learning about how we got here over decades. Well, my talking point going to oncology was that

I was right at this end of the conventional chemotherapy era, as I was calling it, and the beginning of the so-called molecularly targeted therapy era, but it hadn't happened yet. And so I wasn't interested in learning about the past. So in other words, you could see that the futility of chemo, which basically had made minimal progress over 40 years. Wouldn't reach an asymptote, right? So you basically, if you blindly develop drugs against cancer cells to find out what's poisonous to them, and then you filter those in mice to see what kills the mice

at equal concentrations versus what doesn't quite kill them. And you call that your possible therapeutic. What will you get out of that? This is one of my first lectures that I used to give to medical students about cancer therapeutics as I was trying to outline a path forward, is that basically what you get out of that is all these agents that tangle the DNA and some microtubules stabilizing and destabilizing drugs. And the blind approach only gave those types of therapies. Those types of therapies then thrown at cancer cure a good fraction of testicular cancer, a respectable fraction of lymphomas and leukemias, and cure almost nothing

else. Let's pause there for a moment because we're going to just dive right into cancer. But in the spirit of being true to the history, let's just reproduce what you said. So let's take a step back. Many people listening to this certainly hear the terms chemotherapy, radiation therapy. It might be a bit of a fog beyond that. So what you just described was chemotherapy. And what you just described was an arbitrage that must be true. Chemotherapy, it's not hard to kill a cancer cell. It's actually very easy to kill a cancer cell. Yeah, bleach does a fantastic job. Yeah, bleach, formaldehyde, go to Home Depot, most things on the shelf kill cancer perfectly. Problem is they kill everything perfectly. So the arbitrage you described eloquently is it has to kill cancer and almost kill, but not kill,

not cancer. So that's a narrow subset of things. And as you described it, they're targeting DNA for the most part, which is why they're targeting things that grow, which is why when most people think of a patient on chemotherapy, the first thing they think about is their hair has fallen out. They've got sores in their mouth. Their nails are brittle. And if you look a little deeper, you'll understand that their gut is really falling apart. What's common to all those things, right? And their bone marrow cells. Yeah. Rapidly dividing bone marrow cells. That's exactly right. So the analogy I oftentimes use with patients about talking about chemotherapy is it's a bicycle going down the road slowly, one bike going very quickly, one going very slowly. So the cyclist in this case being the determinant of that. And you're standing between two cars with your broomstick and you

come out to throw your broomstick in the front wheel of those two bicycles. One of them goes ass over tea kettle, and the other one looks at you and says, what are you trying to do here, punk? And it's that fast-growing cell concept. It's that filtering system of what can kill a fast-growing cell. That's what generated those hits. We could have come up with other hits potentially. If the chemical diversity of probes that were used were broader, maybe other hits could have been found. For example, we didn't really look at metabolic distinction between them beyond DNA. That Warburg's stuff left behind, we'll come back to it later, but you're right. How to manipulate it particularly was completely lacking. This

concept of you take cancer cells, you establish this mind-blowing ability to grow them outside of a patient and create so-called immortalized cancer cell lines. Henrietta Lacks' cervical cancer being a paradigm example out of Hopkins, but eventually dozens to hundreds to now thousands and hundreds of thousands of these cell lines. Which ones take in plastic versus which ones don't? Well, there's definitely a fast versus slow, So growing just by cancer type. And then within the cancer cell population, which is always heterogeneous, you've got faster and slower growing varieties there too. And the ones that take are these hot rod cells. And if you then use that as your filtering mechanism to ask, well, what will kill them? What you come up with are these toxins to rapidly dividing cells. That's exactly right. So that caps, the term chemo, when I use it, is always to describe these things. Now, important piece of nomenclature is that

people will still always say that, well, a cancer therapeutic is a chemotherapy, right? But no, I favor the way you think about it. I like to think of chemo as that type of chemical. Immunotherapy is used chemicals, but they're totally different, right? Metabolic therapies, PI3K inhibitor, I'm not really considering that chemo, but I want to put a point on what you said, because it's sad, but it's just the reality of it. So when Nixon declares a war on cancer, it's what? It's about 72, 74. Okay. If you look at 10 year survival for metastatic solid organ tumors, so I'm going to just take out leukemia and lymphoma. And as you pointed out, we have seen success in some of those and we'll come back to

it. From a solid organ metastatic perspective, from 74 until 10 years ago, isn't testicular the only success maybe and GIST? Yeah. Yeah. GIST was an early targeted therapy success. So testicular, basically seminobinous testicular tumor. That's right. You could cure with doublet chemotherapy, you could cure the large majority, greater than 90% even. But if a woman had metastatic breast cancer in 1974 and a woman had metastatic breast cancer 40 years later. Shockingly little difference. I mean, we had median survival extensions of maybe six months, 12 months. Yeah. Per new therapy that might come along at best. And then you could stack a few of those in a disease like breast cancer. So what actually kills the population of cancer, breast, colon, prostate, and lung, and then pick up some other

notables that are still refractory to this day, like pancreatic cancer and so on, in terms of number of deaths. But the common cancers, they are perturbed at best a little bit by these agents. So some subpopulation of those cells will slow down and die with conventional chemotherapy, but many of them are pre-wired. They were hardy to begin with. They got there through a hard-earned evolution under selective pressure of the immune system and adverse metabolic environment. And they used all the tricks up the sleeve of a cell, of a normal cell, to reprogram

themselves to be able to survive in these harsh environments. You throw in another harsh environment reagent in the form of chemo, and not surprisingly that these things were already basically hardwired to be able to survive yet another insult. But that's chemo. That's an interesting way you explain that. I think that that's important, I think, for a listener to understand is a cancer cell has to overcome a heck of a lot to get to be clinically relevant. So how many, I used to remember all the numbers and the growth rates, but a clinically relevant mass has how many billion cells in it approximately? Yeah. Clinically relevant that you can find on a scan. Yeah. Like something that you could see, like a one by one by one centimeter cancer.

No, you're in a billion cells already. You're in a billion cells. So just to get a billion rogue actors, you have to evade T cells. You have to grow your own vascular supply. You have to overcome, as you said, adverse metabolic conditions. These things are evolutionary warriors by this point. Yeah. I mean, I usually start, you're absolutely right. I mean, it starts much smaller. These are the filters. Yeah, no, no. But I start with the analogy. There's a random spinning of the combination lock where mutations are being acquired over time through a variety of insults,

or not even necessarily insults, just bad replication technology, if you will, where the detection of errors and the correction of errors is not perfect. Anyway, we accumulate mutations over time, some of which we could limit and control, some of which we can't. Combination lock is just spinning, spinning. The combination has to be dialed in the right sequence, just like when you're opening your gym locker or you don't get cancer. You've got to get your tumor suppressor early and in the right order before your activated oncogene comes along. You're randomly spinning the lock. You're picking up lots of past true mutations, not just true drivers. So these incidental mutations that happen here and there. So as that's happening, you finally click important

components of the program. But along the way, some of those are actually mutations that are seen as foreign by the immune system. And if they're too visible, too far out there, if they're too far out there, then they're gone. So it has to be the right kind of genetic alteration that will give the cell what it needs to be able to proliferate abnormally, to be able to sustain a lot of DNA damage as it accumulates and not commit suicide as a consequence, and be able to handle all the other adverse features and filters of a tumor microenvironment that you enumerated. It has to be able to do all that, but it has to be below the radar, as in not detectable as overly far into the immune system. That's a powerful insight that we only really picked up in the field within the past five years,

this notion that this is not just a cancer cell co-opting its normal cells in the microenvironment in some kind of cocooned way. There are a few cancers that do develop in so-called sanctuary sites that aren't subject to immune surveillance, but the vast majority are. So that is a lot to have to overcome. So there's a chance element on the combination lock spinning, but then there's these, you have to survive the selective pressures that are being applied both within the cell and outside the cell. The relevance of that thought process is highly relevant to how we think about developing therapies right now, but it's also highly relevant to understanding this asymptotic limit of chemotherapy, like how it is that you try to poison this DNA replication process and like just

sort of shred the DNA a bit more. Radiation, the same concept. I mean, radiation even more limited in that it's not systemic. Yeah. So basically radiation became a great tool to locally control cancer. But now you've basically reached an asymptote at the two of the three pillars. And you could argue the third pillar being surgery, also asymptotes at your alma mater. I mean, basically when you look at one of the most complicated surgical procedures for cancer, which is removing the head of the pancreas, that was an operation that used to carry a 50% 30-day mortality, meaning the surgery was, you had a 50% chance of living through the surgery

and the post-operative course. Today, that's 0.1% mortality at 30 30 days but long-term survival is still abysmal so cutting tumors out matters a lot especially for colon cancer i would say is the poster child for where cutting cancer out really makes the biggest difference in even a metastatic disease yeah yeah it's a huge benefit other cancers frankly i'm still not even convinced not to say we shouldn't be cutting them out we absolutely should but it's not clear to me, for example, when you talk about breast cancer, if the dye is cast long before the mastectomy is done and that local control, I don't know anymore. Yeah. We're learning so much more. Again, as our sensing technologies can continue to elaborate because this issue of how many patients already have metastatic disease at the time of their

initial surgery. And you take 10 women who all have one by one by one centimeter breast lesions that are all going to be, let's assume, make them all the same stage. Some of them are going to make it, some of them are amenable to surgery, in my career has never been less than 40% and is probably more like 50%. As we develop more diagnostic technology, it allows us to understand that there's circulating cells in the blood. Those have a hard time surviving, right? People think about a circulating cancer cell and assume that it's going to succeed. No, no, it's super hard to launch a cancer cell into the bloodstream and actually have it find soil, get out of the bloodstream and find fertile soil. That's a whole different problem. Lung cells aren't supposed to live in the liver. It's not a happy environment for them. The growth factors there aren't. Their native ones, super, super challenging bit of biology

to overcome. But anyway, the point being that there are a large number of patients who have curative outcomes from surgery who had seeding of distant organs, even successful microscopic deposits, at least in animal model data, you'd say that that can happen. And yet they still outlive the diagnosis, which is to say at least it lived decades thereafter and never have a metastatic occurrence. You alluded to this earlier. What do you think it is about the removing the mothership that harms the satellite ships? Well, I think they are fragile, the micrometastases. I don't know how much they're being fed.

That's not so much, say, we have the evidence to support that. But they have a significant task ahead of them to really take and survive in this so-called dormant state and then ultimately awake out of that dormant state. So what I'm getting at is the idea that there's a larger fraction than we would have thought decades ago when surgery was curing patients, but we just assumed that they got it early before it had ever traveled. More and more evidence suggests, no, you didn't get it that early, but you got it early enough because those micromats that were established, micrometastases, they didn't have all that it takes. In another wave, more evolution was going to be needed in the primary tumor to be able to launch now micrometastases that had

all the skills to be able to both set up shop in the first place, live in a dormant state for not just months, but years and even decades in some cases, and then make their way out again. So there's those additional challenges that cancer cells have to overcome or tricks that they have to pick up that clearly just become incrementally more likely the more time and evolution gets to happen in the primary tumor. So I think you just stop the clock in terms of that evolution when you come along and either a patient and their bodies tell them that they have a tumor or it's only found or whatever the diagnostic trick is. So that's the great hope in an area of cancer research that I watch very avidly, but being a therapeutics oriented researcher and that's where my mind always goes.

So let's take stock of where the world was 25 years after the war on cancer was declared. It's the late nineties. The scientific community is on the cusp of fully sequencing the human genome. At this point, we know a number of things, right? I mean, that's when I was in medical school. We certainly understood that cancers are initiated by genetic mutations and everything you've alluded to with respect to genes that suppress tumors and genes that promote tumors, the relationship there is pretty well understood. If you refresh my memory, I also think people understood that virtually all of those mutations were somatic. Did anybody have a hope that the human genome project was going to give us a whole bunch of germline mutations that cause cancer?

No, I don't think we believe that, right? No, that's right. You're right. The spinning of the combination lock concept, the right sequence, Burt Vogelstein innovation in colorectal cancer initially, that was in hand by the late 90s, that basic concept. Now, what was left to be sorted through and a justification for doing whole genome sequencing in cancer was that we didn't know what that sequence might look like across cancer. We didn't know what the spectrum of genetically simple to genetically complex cancers was. And I mean that at the individual cell level, not talking necessarily about across all cancer types. So what I'm getting at is, do you need three mutations to get cancer? Is eight somehow better a number? And by that,

I guess, I mean, just look at a distribution of quote unquote true drivers. So wait, because I sort of know the answer today, but I never actually thought about this then. quote unquote, true drivers. So wait, because I sort of know the answer today, but I never actually thought about this then. In 1999, did we know if the average breast cancer had three versus 30 versus 300 mutations? No. And most importantly, how many- How many were drivers? True drivers. I mean, I'd say true drivers because that term driver is thrown around a bit. And true drivers, what are the essential building blocks? And we'll come back to what essential ultimately means, because I think that has to do with therapeutic vulnerability.

But in any case, yeah, this idea of how many hits did you really need? Remember that Knudsen described this, you know, the two-hit hypothesis, right? And it seems reasonably clear that in very simple tumors, two hits actually might be enough. Now, probably then, I think it's fair to hypothesize. Explain for the listener what two hits means in that situation, because that's a great teaching example. Yeah. So two hits, I mean, as it was initially construed, really was the combination of the inactivation of a tumor suppressor gene, tumor suppressor gene being by definition,

the gene when its function is disabled, cancer becomes more likely. Nearly all of the genetically inherited cancer types that people are familiar with come from having a inherited alteration that partially or completely disables a tumor suppressor gene. We know very few of the opposite, which is the activation of another gene. Oncogene could just mean cancer gene, but in the field, most people think of oncogene as the thing that gets activated and tumor suppressor gene is the thing that gets inactivated. That's the simplistic version of the two of the policies. So you're born with two copies of each gene, and one of them is not working, of a tumor suppressor gene.

And later on in life, just from a stochastic process, you only have to hit it once, not twice, which is far less likely. And that's why these are patients that are getting cancer in childhood and adolescence. And multiple of them over time. New unrelated cancers, sometimes in the same organ. I mean, a patient with- Yeah, multiple colon cancers. Exactly.

They keep starting new cancers over and over again. Now, even in the most genetically simple cases, I would just quickly assert that we have plenty of evidence now that suggests that you get these genetic alterations that can dial the combination lock in the right way. But the simplest genetic defined cancers almost certainly have then a quote-unquote epigenetic, as in not hardwired mutation alteration change as well. So a so-called state change where they occupy a different state of development basically compared to their normal cell counterpart. So if we're talking about a pancreas cell, endocrine cell in the pancreas becoming a cancer, it moves away from its differentiated, fully mature neighbors and does so in a way that's important in terms of its

cancer biology. It makes it more hardy, makes it be able to survive insults, makes it be able to adopt programs that it's not supposed to have, like traveling, as in becoming metastatic. More and more evidence suggests that, yes, a lot of that work is done by mutations, but then the mutations, in some cases, actually make the cells more plastic, make them more able to read parts of the genome and use parts of the genome that that cell type isn't normally supposed to have access to. This is an insight that I think has only come... Yeah, we didn't know that 20 years ago.

No, I didn't know in the late 90s. This is my argument in retrospect about what it is that the Cancer Genome Atlas really uncovered for us. A criticism is that we just relearned a lot of the same things we already knew. We already knew that RAS mutations occurred in 25% of all cancers, and we knew then and pretty much know now that we can't drug them directly. So that's an inconvenient reality. The point being that the catalog of activated oncogenes had actually been largely resolved one by one by one from the mid 80s going up to the late 90s. This was the catalog I was looking at when I was saying, I'm going to go into the field and try to figure out how to take this information and turn it into some version of first therapy. I was a student at Hopkins when HIV was absolutely

uncounted with any therapies at all. I did a second sub-internship on the service where the HIV patients were cared for as inpatients usually. That was on the Osler service, wasn't it? Exactly right. And AZT was in humans in clinical trials for the first time. It was talked about actively on that service because it was definitely a research-minded service. So by the time I got finally in through my medical training into oncology, a few more years had passed. So you nadir, I mean, the nadir, meaning the nadir of despair, the peak of hope would have been 96 when heart was introduced, right?

That's right. And that's when you were starting medicine. So I was graduating from medical school at that time. Yeah, I mean, starting your medicine residency right as heart was introduced, right? That's right. And that's when you were starting medicine. So I was graduating from medical school at that time. Yeah. I mean, starting your medicine residency as heart was introduced in 96. And so my talking point was we need to find in cancer as many AZTs as we need as the initial foot in the door. We know we're going to see resistance in this much more complex entity that is a human cell that's gone rogue versus relatively simple virus. But it's when we poke it with the AZT equivalence, we're going to learn about how it is that it tries to adapt. And that's

going to allow us to develop rational combination therapy exactly the way the HIV field does. I still say that in 2019, and it still hasn't really happened. I was about to say, when you were saying that a second ago, I was thinking that doesn't sound that naive. Earlier, you said you had this very naive point of view. It was naive in the sense that with no single example, being able to drug an oncogene, so an activated gene, nearly all of the drugs that people take are inhibitors of something, as opposed to activators. We have some activators in medicine, but not that many. So if you think about cancer and its genetic assembly, then and now, we don't know how to restore the function of something that's lost,

particularly if it's wildly genetically disabled, to the point of even missing from the DNA of a tumor cell in some cases. We don't know how to replace that. This was the hope of gene therapy, the dawn of my career, that we might be able to figure that problem out. We haven't figured it out by a long shot. Inhibiting things that are activated, that has been where there has been success, A, in all of medicine and B, in oncology. So could we catalog activated events and target them with drugs successfully and have these AZT moments? The headwind against that and the reason why people kind of smirked or smiled at my pitch, this is when I was applying for medical oncology fellowships and saying these very, I think, truly simple-minded concepts, was, kid, do you understand how complex

cancer is? I mean, you poke it with a stick, it's not going to care about blocking one thing. I mean, these things have an inordinate number of tricks up their sleeve, like no way. Right, to think that you're going to poke it once and everything will remain unperturbed except that one thing. And then. The idea that that would actually help a patient and that you could learn from it. Both things I think were absolutely not accepted. You remember the first targeted therapy success in cancer.

But the concept, the concept translationally makes sense. I think, I guess what people were bristling against was the notion that, oh, and by the way, in the next three years, this is what I'm going to do. Yeah. Right. was the notion that, oh, and by the way, in the next three years, this is what I'm going to do. Yeah, right. And doing this in humans, as opposed to the laboratory, wet lab, relying on reduced model systems like immortalized cancer cell lines or some other newfangled approach of a reduced system in the lab, that saying that doing this in humans was going to be the way to make fastest progress, that job description hadn't been created yet. So saying that I wanted to do it, A, and I wanted to do it in people, that's what made people fur their brows, which was fine.

That really didn't slow me down because I just, I kind of intuited that at least this is going to be a thing to get out of bed in the morning to do. So you did your residency at the Brigham and then your med-onc was at Penn. Was Carl June there at the time? He was. So let's take a detour into immunotherapy for a moment because there's part of me that just like wants to do this temporally because of how much we know today. And I don't want to lose stuff that we now take for granted, but at the time was so important. So there were a couple of cancers. Well, let's go even further than that. Based on everything you said a moment ago, it's pretty clear that we need systemic therapy. We've reached the limits of local therapy. So surgery and radiation work pretty darn well when they work, but there ain't a lot of ways

to make it better. Yeah. You can minimize their adverse effects. Exactly right. You can make them less harmful, but they're about as efficacious as they can be. We take our first type of systemic treatment, which is chemical chemotherapy. And as we basically saw from 25 years of 74 to 99, we basically cured one additional cancer. Somewhere along the way, there's another idea for a systemic type of therapy. And you alluded to it earlier, which is, look, I mean, you didn't say it explicitly, but I'm just going to put words in your mouth. Once the mutations happen to cancer, they cease to be purely self. They start to display a little bit of non-self characteristic. And we have this branch of the immune system that is, I mean, staggeringly effective at eradicating non-self things,

namely viruses. So we don't have to go back to Cooley's toxins, but basically if you just go into the nineties, you've got guys like Allison who are working on things called checkpoint inhibitors, which we're going to come back to. You've got Steve Rosenberg at the NIH, who's having limited success in melanoma and renal cell carcinoma. You've got Carl at Penn and a number of people around the country that are starting to show little cracks in the armor of cancer. And these results, well, I want to talk about the durability of them, but just for a moment, explain what cancers were we seeing this in and what did we know by the late nineties about immunotherapy? Yeah. So what you just described, one way of rephrasing it is that you had people recognizing this idea that there's a backup a step

what had been recognized pathologically decades before was that there are some tumors that at the time of surgery are evidently visible to the immune system because you can find a ton of immune cells infiltrating into them i mean i like to go back to melanoma many instances there's a good entry in there because melanoma is the cancer type that I have focused on throughout my career. Fortuitous for a couple of reasons, that choice. But in any case, it's definitely useful for this discussion. So what's useful about melanoma in this discussion, let me just remind listeners that melanoma harbors just about the largest number of mutations per cell of a tumor that makes it, if you will, succeeds in becoming a cancer. It flies as high as possible beneath the radar.

That's right. There's a few other cancers out there, but it's a simple reality that they're picking up so many mutations, these melanocytes, the precursors to melanoma from ultraviolet radiation, the vast majority of which we think are useless to the formation. What's the typical number of mutations in a metastatic melanoma? It's high thousands. So you can have in the tens of thousands, but high thousands. There's a distribution and a limit to that distribution. Aren't there only about 20,000 genes? Oh, I mean individual. Oh yeah. You'll find multiple mutations per gene in a melanoma. So on mutations per megabase and then scale that out to the... And how many of those do we think are playing a functional role? We don't know. Five, six is a rough estimate based

on real functional evidence now. So you have this huge onslaught of mutations, which are useless to the cancer's purpose, probably adverse for the purpose of immune recognition. And so it's an outlier. It's not a completely separate, but it's at the far end of the spectrum in terms of cancers that aren't cleared and eliminated by the immune system and survive with all of this mutational abnormality in them, a lot of non-self. So that's a cancer that at the time of initial diagnosis, a superficial melanoma on the skin, you will find, not in all cases, but in the vast majority, a robust amount of immune recognition,

infiltrating immune cells and T cells that are the variety that can clear a virally infected cell and can kill a cancer cell. When they see that the internal contents being presented on the cell surface by the so-called MHC complex have enough difference from self, then that's the cell population that you will witness in those tumors. And it had been described in the 60s that a melanoma, notably other cancers by the 80s, you looked at a spectrum of melanomas. Those that had the most robust immune cell infiltrate were going to be least likely to be life-threatening to the patient after adjusting for other factors. In other words, was the experiment ever done when you took 100 patients who had a local resection, normalized them for depth, so they're all Breslau 5, and you add up the till, tumor-infiltrating lymphocytes, and you get a prediction of who's

going to be alive in 10 years. That's right. Powerful, very powerful, that prediction. And then that was just replicated across the rest of cancer. That finding, colorectal cancer has its own distribution in that regard, and some that are wildly mutated, immunogenic. Has anyone commercialized this today as a diagnostic at the time of therapy, diagnostic or predictive tool? To a degree. So immunoscore is a commercial assay that's been developed that is about more complex version of immune recognition than just these T cells. But we can unpack this more deeply now, cataloging the success, the huge waterfall event in the immunotherapy development era when PD-1,

PD-L1 interactions were discovered and then leveraged as a therapeutic. That fraction of cancer patients who are one drug away from clearing their tumor with a PD-1 antibody, which is the largest impact we've had with an immunotherapy of any kind by a long shot, in terms of numbers of patients helped. These are those patients. Yes, their cancer succeeded, but they had the immune system nibbling at their heels at every step of the way. So yes, they developed a true bonafide cancer. We just had to block this one checkpoint inhibitor. This one break on the immune system where the foot was being expressed by the tumor cell and literally reaching across the divide and repelling or making quiescent a T-cell that had succeeded

otherwise in making it into the environment. That's a swath of cancer. Now it's interesting too, when you go, like I'm much more familiar with CTLA-4 because that was the work, what I was doing when I was doing my time in the lab, both in medical school and later and residency. It was interesting the amount of autoimmunity you saw as well, suggesting that, boy, when you took the breaks off the immune system, it didn't just want to kill cancer. It actually wanted to kill a bunch of things. Yeah. So this reminds people these systems were not created purely to survey for cancer and eliminate it, right? So the purpose of dampening effects on the immune system are that you don't just mount an immune response and have it just take over your body, which is what a CTLA-4 blocking, well, transgenic experiment will produce is lymph

proliferative overdrive that kills the mouse. So the idea that these breaks exist for a reason, I think is intuitive if you think about the fact that basically we live in a complex system. We're exposed to pathogens. We were talking about viruses, but we're being exposed to microbial pathogens that are trying to infiltrate all the time. You wipe out someone's immune system with chemotherapy or a bone marrow transplant, and those bacteria that are living in the gut and- Seemingly harmless in symbiosis. Exactly. They will then infiltrate. They're right at the margin to begin with. They'll infiltrate and they'll take over. This is a really active border zone that's being policed all the

time. You give a C. telifluor antibody, and where does the most life-threatening chaos erupt? It's at the gut. You've unleashed this pre-existing force that's at work all day, every day in this very immunologically active environment. And it starts attacking normal colonic tissue and can perforate the colon from which patient then dies. So leading cause of death from that therapy is rare as those events are, but it's very powerful sign of how this sort of gas pedal and brake component is at play. Play back the conversation to talking about chemotherapy and this notion of therapeutic index. Well, here's the issue with unleashing the immune system systemically with these types of therapies. Yeah. The early days of this in the 80s, when Steve Rosenberg and his colleagues were using mega doses of interleukin-2, you saw that flip side, right? Which was the systemic

inflammatory response syndrome was as life-threatening as the cancer. You were teetering between the patient dies of what looks like sepsis versus the patient dies of cancer. And you have to thread that needle. Right. Sepsis in a bottle. You start dripping in interleukin-2. And the only other time a human being sees that cytokine at levels like that is when the immune system says, screw it. We've got to go all guns. We're going all nuclear. All guns blazing or else the host is going down here. And there's a 50% chance we're going to kill ourselves in the process, but so be it. But this is our last shot. And with interleukin-2, thank God, you can turn it off. And within certainly hours, but even minutes

in some cases, like that whole storm settles down. But the cytokine era, that was the first wave. So coming to your point about how do we get- Yeah, there's a great proof of concept. Yep. But narrow therapeutic index, as in the asymptote was reached awfully early. What were the cancers that responded? Melanoma. RCC and renal. Yeah, melanoma. Melanoma that has the highest mutation burden that didn't cover kidney cancer. Kidney cancer, for reasons that we're still trying to unpack, is very immunogenic. It is highly visible in the immune system. When you diagnose a kidney cancer at the time of surgery, the amount of infiltrating immune cells, active immune cells, so-called cytolytic T cells that are like churning out the enzymes that will kill their neighboring cancer cells. That actually scores at the top. I understand why we see it in melanoma. Why in RCC?

Not known because it's not mutation burden driven. If you look at mutation burden in relation to this immune recognition, there's a very strong correlation across all of cancer with a couple of outliers. And RCC is the renal cell carcinoma. It's an outlier on that curve. Yeah. It's immunogenic without a high mutational burden. Precisely. And how much of this is epigenetic then, as opposed to genetic, that's the piece that investigators are currently trying to uncover. Admittedly, renal cell carcinoma, because of its relative rarity, doesn't draw that much attention, whereas so much more of this work is being done in the more common cancers. But there's a story here across cancer that there's this whole issue of what determines visibility of the immune system

versus invisibility, right? These successful cancers have to find cloaking mechanisms. They will not succeed otherwise. One cloaking mechanism is just stop presenting antigens. Don't make MHC complexes that present these mutated antigens. And if you go high enough up the mutation scale... We'll go so far in this that I want people to be comfortable with the lingo. So what's MHC class one to what is antigen presentation? Maybe do pretend this is a group of first year college kids and you've got a few minutes to explain how T cells work basically. So the major histocompatibility complex MH MHC, is this machinery that exists. These are cell surface proteins.

They become cell surface proteins. When they're first expressed in the plasma reticulum as all proteins, when they're initially translated into proteins, they have the opportunity to sample internal contents, protein fragments, basically. So they're sampling all the time the protein fragment repertoire. And MHC class one and class two, and we each have a portfolio of them. We inherit the diversity of these ultimately from our parents, but we have a massive diversity of them that we're born with.

So class 1 and class 2 can hold different size protein fragments. They're fundamental difference. And there's a flexibility or a nimbleness in terms of class two, which can hold longer peptides. It can see potentially bigger repertoire than class one. So the analogy is your job is making sure a house is okay. There's a house party, the internal house, internal house. Okay. And you're kind of the guy that got hired to help make sure the house party doesn't get out of control. And you're roaming around the house looking to try to figure out, do I need to take any of these guys outside to show the police? That's right. So the immune

cells that are not only activated, not only T cells, other immune cells are interviewing normal cells constantly and effectively all organs. So this surveillance process is happening. We think viral pathogens are what created the evolutionary pressure to evolve this system. Cancer couldn't have been the excuse, right? If cancer is distributed across ages 40, 60 to 80, it's not relevant because you've reproduced and you've served your purpose. So we benefit from having this system that evolution handed to us from viral selective pressures. But in any case, so the system was tuned for that, for picking up viral pathogens inside of cells, being able to present them on the cell surface. So we'll use an example, sorry, just that everyone

will get. When you get a virus that gives you a sore throat, for example, the pain you're feeling, the soreness of your throat is the inflammation. It's the actual endothelial cells within your throat that are hurting because a virus has got in there. The virus has hijacked your DNA replication system. It's doing its nonsense because that's what it does. It wants to survive. It can't make its own DNA. In the process, new proteins are showing up inside a cell. And these little antigen presenters are saying, I don't recognize this. I don't think this belongs in here. I'm going to take it to the surface and let these guys that come by who are... We think the interviewing happens even with normal proteins. So normal proteins will be shown as well as abnormal proteins, not only... That's right. And then it's the cop who's coming

by who has the ability to go, that gun's okay, that one's okay, that one's okay. Whoa, that one, we actually need to go in the house and rip it up. Exactly right. And it turns out that when MHC complexes are presenting antigen, turns out that differences even in a peptide fragment or protein fragment, the position of the abnormality matters. And if it's in the middle, that's able to be seen more efficiently. Some of these principles now have been reasonably well elucidated. So it's really nuanced interview technology. So a ton of normal self that's being seen and excused. And then there's the chance then that some of the abnormal proteins, viral pathogens,

and then mutated proteins as well can be presented and seen as non-self. But I do want to just jump quickly to mention a point, which is that, well, if cancer is developing all these mutations and quote-unquote trying to become a cancer, what might be a trick that you could use to try to evade the immune system? How about if you disable this machinery? How about if you just don't allow MHC complexes to be made? Right. So a cancer cell is, instead of a cell that gets infected with a virus, although notwithstanding that's how some cancers start, if now the cancer cell takes over the entire DNA replication system, the smartest thing to do is say, of course I'm going to make proteins that are foreign. I'm just not going to get them presented on the MHC molecules outside. I'm not going to let anybody outside of me know what's going on inside.

Right. So you might think a virus would have figured this out a long time ago to suit their purposes. Maybe they would figure out how to wipe out MHC complex presentation. It turns out natural killer cells don't like that very much. This is very primordial branch of the immune system that we think about innate immunity, adaptive immunity as being primordial versus more modern, quote unquote, higher organisms having them. Any case, these natural killer cells, which are part of the more primordial immune surveillance machinery, if they see a cell not showing MHC complexes, that targets that cell for destruction. So it's not okay in a fully civilized ecosystem of all cells playing their role and being willing to be interviewed. It's not okay not to make MHC

complexes. So it's thought to be intolerable, if you will, at least in the face of natural killer cells to do that. Otherwise all cancers would like, they'd have figured that trick out long ago. There's this really fascinating story that's emerged in trying to understand the features of cells that will survive the onslaught of an activated immune system after checkpoint therapy, PD-1 or C-Cellulose 4 therapy. Some patients will clear their tumor and they're cured. There are those who don't clear their tumor and they're not cured. And under selective pressure of a- Meaning they undergo a complete response, but then they relapse or they only undergo a PR and never CR. Yeah.

Amazingly, if you look at the data with the PD-1 antibodies, which are, again, that's the thing that's really helped humanity, there's large numbers. I usually summarize that to say that there's 10% of cancer patients currently are getting a heroic benefit from that therapy. There's a higher percentage who get some benefit, like actually double the number, 20%, who do respond. Enough tumor cells are killed by the activated immune system that the tumors will shrink. Under that selective pressure of now heightened immunity, remember there was already baseline immunity to a degree, variably, yes,

across cancer, all cancer types, but still now this activated immune system has just been raging. Those that survive, what do they do? Well, it turns out they start to dial down their MHC complex expression through genetic and epigenetic means. Just enough to satisfy the NK cell, but no more. Precisely. Exactly. So they find this new homeostatic set point. And this is true in metabolism and other programs in cancer, that they find new set points under selective pressure of the onslaught, in this case of activated immune systems, but it could be other oncogene-targeted therapy does a similar thing. Actually, more and more convergence as opposed to divergence has been emerging in the cancer therapy resistance world where even melanoma, for example, where we have effective oncogene-targeted therapy and we

have effective immunotherapy, there's more and more evidence that actually what survives both is the same sort of phenotype, if you will. Cancer's adopting and more evidence that actually what survives both is the same sort of phenotype, if you will. Cancer's adopting similar programs to be able to try to survive the onslaught, even from those two very different modalities. Do you think it's safe to say that the lethality of cancer is directly proportional to that evasion? For example, why is it that when you take the ratio of people diagnosed with pancreatic adenocarcinoma to people who die of it, contrasting that with something like prostate cancer? Now, prostate's a tricky one because it's sort of immune protected, but maybe we can pick an example that's less.

Glioblastoma is right there with pancreas. Although for a totally different reason, right? It doesn't really metastasize. I mean, it's causing most of its local destruction. And it's in a bad spot. Yeah, yeah. It's in a space-restricted... You're right. But it is fair to say, though, that both pancreatic cancer and glioblastoma are really not immunogenic on the spectrum.

Prostate, as you say, is out also in that end of the spectrum. So if you just look at this baseline at the time of diagnosis, how much immune recognition is there, how much does that relate to how long someone lives and how likely they are actually to respond even to conventional chemotherapy, you can splay cancer out, all cancer types, and there's heterogeneity within cancer types as well. So not all lung cancers are the same. And you can come up with some of these that are, as you say, they are aggressive tumors. They're not being seen adequately. So not being slowed or being nibbled at by an immune system in their evolution. And then at the time that we diagnose them to the time of death, basically almost nothing happening

there either. Do you teleologically have a rationale for it? I mean, we didn't come up with a good explanation on why RCC, renal cell carcinoma, would be so immunogenic despite the relative positive mutations. At the other end of that spectrum, what is it about a pancreatic endocrine cell that would allow it or have it be so protected? Yeah, this is a black box at the moment. What you're asking is the fundamental comparative biology question in cancer. That's this decade. Yeah, I leapfrogged us past 2010. We are now wrestling with this opportunity to do comparative biology, not just experiments, but analyses. I mean, what are the building blocks, genetic, epigenetic, the metabolic features? How did each of these tumors assemble themselves to be able to accomplish

the various behaviors of cancer that make them lethal? I would say this is where we have more black boxes in diseases like pancreatic cancer and glioblastoma anyway. The hormonally driven cancers are a unique entity, right? So prostate cancer is almost all hormonally driven, at least at its outset. It can evolve away from hormonal drive slash dependence during its subsequent evolution. And then a significant portion of breast cancer, but not all, is hormonally driven. Those cancers need to be considered a little bit separately because they're still using this lineage dependent tissue of origin dependent program of using the feeder, the hormone to help achieve its purpose, if you will, always going back to anthropomorphic concepts and cancers, just how I've always thought.

Cancer and immunology are so geared towards that way of thinking. Yeah, that's right. Yeah. It's immune cells, exactly. You readily put yourself in the driver's seat, if you will, in terms of various immune cell types. Everybody likes to be a CD8 positive T cell, I think. But I'd rather be CT4. A helper. A CD4, yeah. I'm more of a helper cell. Right. Any case, now to answer your question, if we had better insights into this, we would have more hypotheses moving towards therapeutics in these cancer types. But the have and have not spectrum in cancer is only getting wider. The advances that have been made in certain areas where we've very clearly fingerprinted the top of the pyramid vulnerability, it's not just about

mutations. I mean, it really is about other cancer programs that are at the forefront of that cancer slash cancer type. The AZT equivalent has been worked out to dismantle that one program. It doesn't cure everybody, but it helps patients directly, perturbs the hell out of that cell. And I still maintain the hope and I guess belief even, if I'm allowed to use that word in a scientific discussion, that secondary vulnerabilities are going to come from being able to have enough AZT-like primary interventions or points of vulnerability. But you said something earlier that I want to repeat because you've alluded to it twice, I believe. It's a bit of a scary concept, right? Which is

some of these mutations may have no obvious, immediate, targetable quality, but they enable epigenetic change that itself is the problem and much more difficult to target. Is that a fair assessment? That's right. I dropped that thread from before. I meant to finish a thought previously that the Cancer Genome Atlas Project, like whole genome sequencing of large numbers of cancers, what did it teach us? Well, it retaught us what we already knew in terms of the common tumor suppressor genes and activated oncogenes. The big discovery was how commonly you will find across cancer driver genetic events, so the causative genetic alterations in genes whose protein product regulates chromosomal well-being. So epigenetic regulators, as they're oftentimes thought of. So chromosomes are complicated. They're dynamic in normal cells, and they're definitely dynamic in cancer cells. Think of it as a folding and unfolding of the blueprints. Basically, certain cells in the body only need to read one segment of the blueprint to be able to do their job. Cancers, generally

speaking, like to open up the blueprints. That's a fair generalization. And you can reflect that even at this, the entire chromosome level, literally chromatin is open and being read more actively. It's the only way that a lung cell can figure out how to travel like a white blood cell ultimately is you have to open up the blueprint and see that part of it. genetic regulators that are being, that now were really discovered by the Cancer Genome Atlas Project. So going back now, I guess 10 years ago is when it really kind of these insights first began about five years ago. That era taught us how widespread these types of genetic alterations were. That was not known before that campaign was launched. So yes, you have these activated events, these tumor suppressor genes that are eliminated. Many of them have to do with DNA repair mechanisms and talk about other common tumor suppressor genes. But anyway, in the middle are these epigenetic regulators that themselves are activated or inhibited through genetic alteration.

That was just a big aha moment in the field because it showed how essential, well, A, how cancers do it, that they create this so-called plasticity, this ability to basically go from being a differentiated lung cell into a less differentiated lung cell that's not now able to do things that its normal lung cells are not supposed to do. It gives up some of its lung superpowers in exchange for greater pliability. And yeah, it's just, it's like a reality TV show you couldn't make up. Yeah, it's diabolical, but it's using the whole playbook, right? I mean, I use that blueprint analogy, but it really is, you know, every cell in the body has the entire chromosomal content in it.

It just doesn't use it like that discussion in neuroscience about how much of your brain do you use at any given time? Well, the normal cell isn't using so much of the blueprint to do its job. If it's going to become a cancer, which is a cell doing many jobs all at once, and to the detriment of the host, ultimately, it really has to open up and maintain this open blueprint, not just wildly open, but very, you know, kind of strategically and purposely. So that happens, again, relatively recent insight. We are just at the beginning of actually developing tools as in like chemical tools to actually alter

the function of these proteins to see, well, then what would happen? Can you actually restrict the blueprint reading? So go back to melanoma one more time. Melanocytes derive from the so-called neural crest. So the brain tissue and these pigment producing cells, like super weird developmental fact, come from the same tissue type. So, and melanocytes, as people probably well know, distribute generally just throughout the sun-exposed skin, although there's a few stragglers here and there, which can form melanomas. Any case, these guys are sparsely distributed in the skin, creating a little bit of a shield of sorts, but not a very effective one. Any case, they derive from the neural crest. That's where

they come from. So, what happens when you blast the hell out of a melanoma with BRAF-targeted therapy and a PD-1 antibody and you're shrinking tumors down but not eradicating the cells and things come back out? What do they start to look like? They look like neural crest cells. developmental path, and in doing so, find hardiness mechanisms that allow them to survive an activated T-cell repertoire, allow them to have their dominant driver activated oncogene largely disabled, and be able to manage, not only survive, but ultimately then begin again growing and becoming life-threatening. This is a theme across cancers. I mean, this has been seen now, lung cancer and breast cancer and other tumor types where there's been substantial advance in terms of therapies and real outcomes being achieved for patients. So these leapfrog moments that have been happening, common, common principle is this so-called epigenetic state change thing. And the genetic

determinants of it, as I said, are really, it's within this past 10 years that we've gotten any insights into it. When we talk about targeted therapy, it's a bit of a buzzword now. And I think for someone like you, it's worth maybe clarifying how do you define targeted therapy and what do you think is really our first great example of it? Just to get right through the jargon and be able to keep chemo to one side and targeted therapy to the other. What I've always said is targeted therapy is simply that we knew what we were doing from the beginning. So we knew what we wanted. We knew what the specs were. It's Babe Ruth actually pointing at the wall. Exactly. Everybody can hit a home run. Not just closing your eyes. That's right. But if you can actually point to where the ball's going to go before you hit it. So it's basically none of the conventional chemotherapy drugs were known to be DNA binding

and designed and engineered to be them. But the target product profile, if you will, was spec'd out for everything that we call targeted therapy. Now, some people might take exception with that, including the first monumental success. So we actually had two versions of targeted therapy at work in the 90s, somewhat quietly. Epidermal growth factor receptor and HER2, which is related in the same family, close-knit family actually of epidermal growth factor receptors, plural. These two surface growth factor receptors had been kind of discovered and cataloged in terms of their biologic function in many cancers in the 80s. And then antibody that could reach the cell surface component of these receptors were engineered and were being investigated in clinical trials. They weren't causing heroic effects as had been hoped, but those were definitely targeted

therapies. They did end up moving the needle and largely in combination with conventional chemotherapy, notably in the case of HER2 targeted therapies in breast cancer and EGFR antibodies, at least in colorectal cancer. And before we leave HER2 new,geted therapies in breast cancer and EGFR antibodies, at least in colorectal cancer. And before we leave HER2-neu, what's the success rate? So if a woman, HER2-neu is used pretty commonly as an adjuvant now, right? Yeah, but the naked antibodies produced a 10 to 20% response rate. So tumor shrinkage by the criteria that we use in clinical trials. Yeah, so more than a 50% reduction. Yeah, so notable benefit in a pretty small fraction of patients when given as monotherapy. When given and given in patients who still had disease.

That's right. Initially in patients with overt metastatic disease, overt versus covert metastatic disease. So that's right. So is that really an AZT-like moment to see that type of tumor shrinkage depth slash reliability or unreliability of tumor shrinkage in that low range? depth slash reliability or unreliability of tumor shrinkage in that low range. So to be debated with conventional chemotherapy, which itself had a 30, 40% likelihood of causing the same amount of regression. And then you are now in business because you're producing 60 plus percent response rates. Now, these are mostly PRs, not CRs?

Correct. PR is partial response, CR complete response. And in every cancer type, it's true in leukemias or hematologic malignancies, as is true in solid tumors. The more you can beat down the tumor, the more likely that's going to last for a while. So putting people, quote unquote, into remission, which is a leukemia term, actually has its solid tumor equivalent. So complete responses are the most durable. Surprise, surprise. And amazingly, even our kind of stupid CAT scan technology, as much as we think, oh, I can only pick up a smaller than billion, but many, many millions of cells needed to be visible on a CAT scan. It turns out that actually that threshold, the clearing below that threshold, the so-called complete response, actually does mean something very powerful in terms of patients' longish term outcome. Maybe not cure, but still longish term outcome, even with certain monotherapies.

So HER2 was an example where, yeah, move the needle to a degree in a subpopulation. With conventional stupid chemotherapy, it seemed to actually collaborate reasonably well and improve survival in big phase three trials when HER2 antibody was given with chemotherapy versus chemotherapy alone. That was a slow-motion aha moment. What was the fast-motion one was the, to me, kind of validating moment, which was in BCR-ABL translocated chronic myelogenous leukemia. And then the same drug amazingly worked in gastrointestinal stromal tumor. But any case, that came a couple of years later. So what, explain what's a tyrosine kinase? What is that whole thing that you just said and

why does that matter? Right. So the chronic myelitis leukemia. So there's four leukemias, broadly speaking, right? Acute and chronic myeloid and lymphoid leukemia. Kids are more typically getting the acute ones, both lymphocytic and myeloblastic, correct? Yeah. Turn that around. Pediatric cancers are rare, generally speaking, but it turns out- Sorry, when a kid gets one, it's more likely. Bomer drive cancers are a common problem for kids. We think that actually relates to the number of hits, by the way. Like if you're a kid, you can't accumulate that many hits. And so cancers that can form with few hits are the ones reflected in the pediatric population.

So exactly as you say, those things, they're built on few hits. They're rapidly, acute leukemias, rapidly dividing cells. And you can cure them, kids, greater than 90% with multi-agent chemotherapy cocktails. Yes, that make them sick, but you can cure them. And there can be long-term consequences. So I'm not trivializing the room for improvement there. But anyway, chemo definitely in pediatric acute leukemia is a big deal. Chronic leukemias happen very uncommonly in kids, but can happen.

Adults more commonly get chronic leukemias, but can also get acute leukemias that are more genetically complex than the kids' versions notably, and therefore harder to cure with the same exact chemotherapy regimens. So one form of chronic leukemia, so-called chronic myelogenous leukemia, so in the quadrants as you were depicting them, this is one. People could live with it for five to seven years. If you replace their bone marrow, so-called bone marrow transplant, it could cure a minority population. On a good day, maybe 40% of CML patients can be cured with bone marrow transplant. But a molecular insight came in the 1970s that basically there was a very common kind of macroscopic, if you will, chromosomal change where one part of a chromosome would very

stereotypically, 95% likelihood that a CML patient would have the repositioning of one portion of a chromosome to another. Which is kind of hard to imagine when you think of how big that is. Yeah. Right. Like big migration. Everything we've been talking about is this base pair, like maybe it's worth it. I think most listeners know this, but it never hurts to be reminded. Can you walk from the scale of base pair to gene to chromosome, like just give people a sense of you're on a little spaceship, you get shrunk down, you are entering the nucleus of a cell. What do you start to see as the plane's landing? Right. So we talk about 23 pairs of chromosomes and that really is a biologic reality. Decades

and decades ago, the practice of being able to kind of spread out the chromosomes and fix them in a way that you could stare at them outside of an intact cell is the picture that people have been shown in elementary school. In cells, they really are, they do exist as coherent separated entities, but much more nebulous than how they're splayed out as 23 pairs. 23 chromosome pairs, we get one of each from each of our parents and they range in size. So you got one to 22 looks sort of the way they do and then XX or XY round out the- Exactly. And so their size difference relates then to the amount of genetic content in each of them. It's an important point. I usually go straight to genes, but we can come back to base pairs. So there's 30,000 genes. That's the current number that people-

I got to update my estimate. I've been saying 2025. Yeah, so this is... Coding versus non-coding. Coding versus non-coding. And that's still, even if you include non-coding, true genes, you still have a lot of in-between material, a ton, a ton. The vast majority of base pairs are function not determined, essentially. Are they important scaffolds? Probably, at a minimum. They're least scaffolds. This whole notion about opening the blueprint, closing the blueprint, they probably play an important role. Much of the genome probably plays some role in that opening,

closing process, normal and pathophysiological. Any case, so you think about the number of total genes that exist and the size of them and the amount of genetic code that's in them versus the dark, quote unquote, dark matter, at least scaffold, maybe smarter scaffold than we give it credit for. There's relatively small portions of it that we actually understand. Really, coding genes are what we at best understand. Which is why when somebody does a 23andMe sequence where for a hundred bucks, I mean, you can pretty much, I mean, you're not going to get a complete sequence, but you can get a complete sequence anywhere on the street today. Right. And so usually those tests will hone in on the component of the genetic sequence that we know something about. So you can at least present

fingerprint to someone in terms of their inherent or their ancestry, and then maybe something about disease, but not a lot of insight there. The genes, of course, vary, individual genes amongst the tens of thousands vary enormously in their size and therefore the amount of genetic code in them. And the mutation opportunity, of course, we think is to a degree equal opportunity. I mean, you can develop a mutation either because of a replication error or because of an insult. So the larger the gene in theory, the greater the probability it can acquire a mutation. Sure. And p53, the most famous tumor suppressor gene of them all. How many base pairs?

p53, I don't know off the top of my head. I should Google that someday. We'll do it for you. It'll be in the show notes. Yeah, right. So let's go with ballpark it at a couple hundred thousand base pairs. Big gene, multiple exons that are separated by introns that are stitched together when the gene is transcribed into RNA and then...

And extrons and introns for folks is coding. I mean, it's part that actually gets turned into RNA versus that that doesn't. Exactly. But they still play an important regulating role and again, at least scaffolding kind of stitching together. And that's something that, again, 20 years ago, people thought those introns don't matter. Yeah, they're dead. Right.

Exactly. But that's where all the... Junk DNA. That's where all the regulating elements really largely reside. So it's a huge in the past 20 years, that's been a parallel track, big area of innovation. So any case, so then you have a big gene like P53. So 50% of cancers have genetic aberration P53. Well, partly it's just a really large gene, but so you can pick up mutations, you know, in it seemingly relatively easily, but it's a master regulator.

What percentage of cancers do not have a p53 mutation? 50%. And the other 50 do. Oh, so it's 50-50. Yeah, yeah, yeah. I would have guessed that fewer people with cancer do not have a p53 mutation. Do not. Yeah, I would have thought it was almost essential.

Okay, so p53 is such a complex central node in a very complex network. So there's tons of translated proteins that interact with the protein product P53. And then P53 has a lot of outputs, like literally networks of outputs. It's in cancer, any case, I would say it is the most magnificent and thus far well mapped out of these networks. What is the function of P53? Very simply put, it's basically a sensing apparatus. It's trying to understand how bad things are in a cell. And usually people would say, well, first, if there was a singular function, it's how poorly is the genetic code doing, which is to say the chromosomal architecture, how intact versus not intact is it, how many mistakes, mutations or mistakes, so insults

versus mistakes, how many of those exist and are being repaired at any one time? Like, so that machinery is at work, the DNA repair machinery that feeds then into P53, which basically is just sensing overall, how well are we doing in terms of kind of... And P53 possesses the power to command apoptosis directly. Yeah. So it senses damage in a normal cell. That's its function. In a cell that's becoming abnormal, it continues to keep its finger on that pulse. And if there's catastrophic damage, then it's P53 that says, let's not try to

repair this anymore. Let's fold up shop and undergo a civilized cell death and let our neighboring, let's say liver cell, just take over and do our job if we're a liver cell. So P53 is the master regulator in all cells in the body. I love doing these podcasts because I still, even it's on a topic like this where I know a little bit, like I'm amazed at how much I keep learning. So 50% of people who get cancer have a perfectly intact p53. Yeah, that's right. Yeah. But the point about describing the network is the likelihood that they will have a genetic aberration in one of the inputs or one of the outputs of p53 is enormously high. Got it. So we say the gene p53 only 50% of the time is mutated,

but the pathway is virtually always hosed. So retinoblastoma gene, you're familiar with that, that's another very famous, long ago described tumor suppressor gene. What was not known decades ago but is known now is that they actually relate to each other and you will find cancers that if they don't have a p53 mutation, they will have an RB retinoblastoma gene mutation. It's another big tumor suppressor gene that actually is quote unquote downstream or regulated by p53. And its alteration will do much of what a p53 mutation will do. So there's these kind of functional substitutes in that axis. On the activated side, that's where I spent most of my career. So KRAS. Exactly. Talking about KRAS. What is this clown doing? So I was just going to say that growth factor receptors, which I touched on before, because

epidermal growth factor receptor and HER2 were these kind of early discovery slash therapeutic translation exercises. Well, that was the beginning of a theme that to this day we think is kind of the biggest unit in terms of where the activating events happen and where we have drugs now is in the growth factor receptor RAS and RAS pathway system. So growth factor receptors, literally their normal function is to receive growth factors. So in a cancer cell, if you can figure out how to grow in a growth factor independent way, then you've accomplished a good trick because now you'll be able to survive very harsh environments. You'll be able to replicate kind of an autonomous, not governed by not just environment in terms of

nutrient availability, but even like what your neighbors are telling you, you shouldn't, shouldn't do. You can ignore that. One of the explanations for why we see more aggressive prostate cancers in men with lower testosterone levels than higher testosterone levels. If your prostate cancer can grow without testosterone, beware. It's a bad problem. And then same with breast cancer, with hormone receptor, positive breast cancer, quote unquote, versus negative. The prognosis and treatment response is wildly different. Much more different. A different disease basically. So that's exactly right. So cancers fundamentally need to accomplish this task. So growth factor receptor genetic alterations, HER2 is genetically amplified,

then like massively increasing the number of surface receptors and allowing them to actually complex together and signal in the absence of needing the growth factor itself. That was the seminal discovery going back even into the 80s, but certainly picked up a lot of steam in the 90s. And then was a validated target ultimately, as I said, in a relatively slow motion way compared to BCR-ABL, which we're going to come back to. So anyway, these growth factor receptors feed RAS, R-A-S, and that comes in three forms, K-RAS, H-RAS, and N-RAS. And 25% of all cancers have a RAS mutation. Right downstream of these growth factor receptors is where RAS sits, just on the inside of the cell surface. We can't drug it directly, certainly with an antibody. Small molecule inhibitors have been hard. That's its own discussion in terms of what's

assailable and what's not assailable in terms of cancer drug targets. But let's park that one and say that RAS is a big deal. And then RAS has its so-called effector pathways. And the numbers, to a degree, I think, how many people agree on the number of cancer-relevant RAS effector pathways? I can't find a lot of consensus there, but six is a reasonable number of described cancer-related RAS effector pathways. So downstream of RAS, RAS will activate other cascades. The two most famous are the MAP kinase pathway, where I've focused my career, PI3 kinase pathway. Arguably, there's more mutations that activate the PI3 kinase pathway than the MAP kinase pathway, but... Lou and I have been trying to sit down for, we cohabitate parts of New York

that are 10 feet away from each other. So at some point, Lou and I are going to sit down and have a lengthy discussion on PI3K. Yeah. This is where I wanted to take a little deep dive into Lou and Craig Thompson's- By all means. Travels in the PI3 kinase pathway.

Here's a pathway in this growth factor receptor signaling apparatus. Metabolic regulation comes, we think, largely, but not completely, through the PI3 kinase pathway. If you link up the discoveries of Liu and others regarding the importance of PI3 kinase in cancer, the fact that 20% of cancers have PI3 kinase, intrinsic mutations in one of the isoforms of PI3 kinase, most commonly alpha, it's a nasty little trick. I mean, it's co-opting this

kind of metabolic regulation pathway. It largely explains growth factor independence of cancers that have those mutations. But these are metabolic pathways that are fundamental to normal cells as well. And so where's the therapeutic index in terms of leveraging that observation? This has been a major challenge and not yet really adequately tackled. But one positive result, at least in PI3 kinase mutant breast cancer that finally came across in slow motion, phase three result. When it takes a phase three clinical trial to be the aha moment, that's a slow motion result versus 20 patients get treated and you know you're in different territory, which was the BRAF example

in melanoma and then other cancers thereafter. So the MAP kinase pathway is this proliferative pathway as it's canonically described, but it does other things, at least in cancer when it's co-opted by mutation. Common theme, by the way, when you activate an oncogene in cancer, very commonly you will see that the downstream wiring diagram changes, and that pathway is now able to do more things than we would have given it credit for or said that it had those same abilities in a normal cell. It's what we mean by oncogene addiction, if you turn it around in terms of building blocks. Oncogene addiction means that cancer really needs that activated oncogene to be able to do not just one thing like drive proliferation, but actually to alter other

essential programs for cancer. The flip side is that normal cells in the body, they have other ways. They can break up the work between proliferation and metabolism between, for example, the MAP kinase pathway and the PI3 kinase pathway. But in melanoma, for example, where we see, we call it kind of this paradigmatic MAP kinase pathway activated tumor, yeah, it cares about the PI3 kinase pathway, but in quite a secondary way. Breast cancer, flip that around. Yeah, it cares about the PI3 kinase pathway, but in quite a secondary way. Breast cancer, flip that around. So this idea that we could actually come up with an understanding of these normal cell processes that are co-opted by cancer, drug them, and do more harm to the cancer cell

than the normal cell, it wasn't intuitive to people. I mean, this goes back to this watershed era of the early 2000s when the concept of targeted therapy finally kind of had its aha moment. It really relied on this concept and the term oncogene addiction, when did I first hear that? I suppose it was in the early 2000s. This idea that by a cancer co-opting this one molecule, it's actually now essentially using it to drive kind of more components of cancer biology than you would have thought in terms of the normal physiologic role of that molecule and where there's compensatory mechanisms and parallel

processing that can happen in normal cells that make it not so dependent on the function of that one molecule. So anyway, RAS, 25% of cancers have a RAS mutation. 20% of cancers have a PI3 kinase mutation. There's a little bit of overlap there. 8% of cancers have a BRAF mutation, which is intrinsic in the MAP kinase pathway. It's the most popular point of mutation in that pathway. What percentage of melanomas have a BRAF mutation? About 50%. And it was that simple alignment of facts. I was finishing my fellowship in 2002, June of 2002, becoming faculty at Penn in July of 2002. In June of 2002, In Nature was described the research project that the Sanger Center in the UK, one of the sequencing powerhouses then and now, they had launched this

campaign specifically to sequence the RAF genes, not RAS, R-A-S, the one that's undruggable, unfortunately, still to this day, but rather the RAF genes. Why did they do this? Because the MAP kinase pathway had been implicated as being relevant in cancer for a couple decades, and no one knew other than RAS mutations that can activate it. Outside of that, no one understood how and why the pathway could be co-opted by cancer cells. So a logical thing to do would be just go one bucket down in the bucket brigade from RAS to the molecule that RAS regulates, which is RAF, three isoforms of RAF, C-RAF, B-RAF, and A-RAF, understood lesser and lesser degree across that sequence. So C-RAF was the first discovered, called RAF1 at the time, then it was renamed C-RAF later. People had

studied C-RAF to a large degree, B-RAF not so much. There were only really a couple slash few B-RAF mavens in the world, and still to this day, not very many ARAF mavens. The hypothesis was that these RAF genes are probably going to have some mutations, and C-RAF would be the one most likely because it'd been the best studied up to that date. So the big headline from that Nature paper was rarely ever do you see a C-RAF. B-RAF was the big discovery. 8% of all cancer was the estimate when they sequenced 484 tumors. A RAF rarely, if ever, mutated. So BRAF was the one. The why of that is its own fascinating little bit of kind of molecular evolutionary history. BRAF and C-RAF are different molecules. Does RAS actually play a causal role in the mutation, or is it more a function of

the things that bug RAS bug BRAF? Yeah, that's true. They're related. They talk to each other. But let me answer it this way. In a cancer that has a RAS mutation, you will not find a BRAF mutation and vice versa. They are mutually exclusive. So you don't need to skin that cat twice.

You do it one way. RAS is sufficient or BRAF is sufficient to get activation of the pathway. Melanomas, for example, 50% of them have BRAF mutation. Very similar to the p53 problem. Yeah, that's right. These tumors anyway need it, and many cancers need this pathway on. How they accomplish it varies, and we don't understand all the determinants of why certain cell types are more prone to picking up certain mutations as their, if you will, their means of activating certain pathways. But there's certainly a sort of teleology argument there. Any case, severe F mutations discovered in 8% of all cancers. I had decided melanoma was a cancer of terrible unmet need. Interesting biochemistry insights coming from the previous

couple of decades, very strong lab-based science in melanoma at Penn, where I was choosing to put myself on the clinical frontier, clinical research frontier. This aha moment in this paper was that 8% of cancers had BRF mutations, but the cancer type that most commonly had them in that paper, later paper described that there's one rare cancer that more commonly has BRF mutations, was melanoma at 50%. And the vast, vast majority of those mutations affected a single point in the gene. So let me pause now to go back to the question so that people understand scale. A point in a gene, right? So you have 23 chromosomes, call it 30,000 genes. Let's make the math easy. You've got about a thousand genes wrapping around each chromosome, order of magnitude.

Okay. So one chromosome has got about a thousand genes wrapped around it. You've got 23 pairs of those. And now each gene could be anywhere from a few hundred to a few hundred thousand base pairs. And what you're talking about is one of those could be mutated. You could get one letter wrong out of a hundred thousand and you change the function of a gene. Exactly. You asked before about kinases and this is going to... All of this is in service of CML. Right, exactly. We're going to link those two concepts. So basically we have, I use that phrase bucket brigades, we have these pathways where one molecule alters another, alters another. We too commonly think of these as linear, one augmenting another followed by another and not as systems where there's side inputs into these pathways, which has been well described, including the

MAP kinase pathway. In any case, follow me here that basically RAS activates RAF. When RAS itself is activated, it pushes RAF into a pair of molecules, so-called dimers, and will facilitate their phosphorylation or molecular feature change that allows them to be active. So kinases are a form of enzyme whose job is to add a phosphate group, a single, fairly small molecular entity to specific amino acid residues on its target. And usually it's more than one target, but the point is that there is a fidelity in terms of that relationship where you've got a kinase and its substrates, plural. So RAS will activate RAF.

RAF will activate MEK. MEK will activate ERK, all through phosphorylation events. So they glom onto each other and find the right domain and stick a phosphate group on People are used to hearing me say that I get phosphorylated. And I think they understand exactly what you're... I can sometimes, my five-year-old can get me more phosphorylated than any tyrosine kinase in the history of our known universe. So phosphate residue additions are, they're not the most important, but they're a key

facet of how the molecular machinery works inside of cells in terms of how to activate or inactivate these networks. And here we're talking about growth factor receptor related networks. So right in the middle of the so-called kinase domain, the part of BRAF that actually is basically responsible for latching a phosphate residue on MEK, its downstream substrate, right in the middle of that domain, I mean literally right in the middle, is where these mutations happen in the vast, vast majority of cases. That discovery alone was just shocking, right? Because by chance alone, you're not going to find, stumble upon these mutations piling up in 8% of cancer.

And there's one point right in the middle of the kinase domain. That wasn't also in the same paper, was it? No, that point was. It was. Oh, yeah. The distribution, if you will, of them being V600 position mutations, a valine at the 600 position in the amino acid sequence, right in the heart of exon 15, which is in the middle of the kinase domain. That was in the paper. The additional killer experiment that they did was to basically transfect that

into a fibroblast, so a normal cell, and show that that could transform them and make them proliferate to a degree. And that was it, kind of end of paper. So the phenomenology that these mutations exist, this wild distribution, or if you will, non-distribution, this like piling up at this one position, it was just this huge aha moment. And when you link that in melanoma with this couple decades worth of insights that the MAP kinase pathway really seemed to be important in this tumor, and now you find these mutations sitting here right in the middle of the pathway, like that was just like the most drop-dead, obviously important thing in my view and a couple other people's view, but shockingly few other people at the time decided to take a complete left or right turn and focus on it. But I was

at the dawn of my career. So this is a problem with biomedical research is that every time a discovery is made, it impacts the people who are in search of substrate precisely who've said, I want to get to the frontier of known and not known. I want to investigate. Everybody else is busy. They're already doing their thing. And if they're grant funded, then forget about it. Like they're already mining away. I think of the lab I was in in 02, 03, 04, it was all immunotherapy. Like we never talked about, I mean, maybe that paper came up at journal club as like one of 50 papers discussed that year is interesting. But I mean, it was anti-CTLA-4, it was till, it was because everybody there was super seasoned, super senior, and they were already on this path. That's a great point. I never really thought of that bias that can exist

temporally through a person's career. And melanoma, for all the reasons we discussed before, had been dominated by cancer immunologists because they recognized that there was this robust evidence of tumor immune interaction. You had this huge opportunity. Yeah. And so the idea that you could just make one more maneuver, be it a cell therapy or a checkpoint antibody or cytokine, and tip the balance and clear the tumor. The field was very focused on that. And if you were interested in the general notion of cancer immunity, well, melanoma seemed like a very natural home for that work. And that really was the subtext. I came walking in with this very different idea. Last thing you wanted to do was do what everybody else was already doing.

Exactly. I'll just finish this point by saying that this is the whole coaching point to the petrified or even paralyzed young trainee who's thinking, well, how am I going to find my entry point? Where am I going to find something to work on? What I say is, okay, you're not waiting for something top secret that someone comes and whispers in your ear. What you're waiting for is the next nature science and cell paper to be published that describes something that's very important in an area that you've said you've just, for some intuitive reason that you have an interest in. And trust me, the field is not going to drop everything that they're doing to go pursue that. But if you're at the dawn of your career, you're in the perfect moment to now actually

build the knowledge base, meet the people who are the relevant players, assemble the knowledge, pull together the tools to actually start testing this hypothesis, whether it's you're a wet lab investigator or clinical investigator, the same. And I've never witnessed a case where someone's been basically crowded out or hasn't been able to make a career in investigation by using that approach. I'm trying to come back to the watershed moment of BCRA, but I'm going to do it this way. So BRAF mutations were discovered in 2002.

People ignored it, not only because they thought tumor-immune interactions were a cooler thing in melanoma, but remember, melanoma is jacked up with mutations. It's got an inordinate number of them. So you find this one. So what? If there's a cancer on earth where we're poking that beast with a single drug approach, just antagonizing BRAF is going to do nothing. This is the example. That was the headwind argument.

Absolutely. In fact, I would say that that should be the null second and third, fourth alternative hypothesis. That is a capital so what. Yeah, exactly. Maybe we'll circle back later. Maybe that's why it wasn't even mentioned in Journal Club. And then when the first putative RAF inhibitor didn't work, this was the other big, ah, we told you so moment, which we, let's table that for a moment.

So chronic myelitis leukemia is fundamentally different. I mean, this was known even in the seventies that if you look at the splay of chromosomes and you see this one migration of one segment. Right. And the listener now understands why I got phosphorylated when you said that so they could understand it. These chromosomes are huge. Like one piece of one of them could literally, it's like picking up a building in a cell and moving it and attaching it to a condo somewhere else. So this was observed by Peter Knoll decades ago. And as a characteristic event in CML, that you would see this in at least 95% of cases, this massive chromosomal shift,

but not others. In other words, it wasn't like the DNA was shredded at the chromosomal level. It was this one migratory move. and it was like characteristic pathognomonic of the disease. That was striking, right? Just that fact. Striking. It's also important for the listener to understand, you could see it under a microscope. Yeah, right. Exactly. Like there's nothing genetically, like all this stuff you and I are talking about right now, you don't look at your microscope and see that. No, you got to sequence individual base pairs and large numbers of them.

This might be the only genetic mutation in cancer that is visible under a microscope. Well, we'll come back to that. There's another example? Yeah, well, fusions in general. Okay, yeah, yeah, yeah. No, that's a fair point. So the term translocation was the term that was used then. Now we use the term fusion. Yeah, my point being anything outside of a piece of a chromosome moving. So fusions is a theme in cancer, their own kind of substrate of discovery. But this was the first one. So basically you had what appeared to be at the chromosomal level, genetically simple cancer, where nearly always one big fragment migrated to

join another big fragment. What was at that juncture? Like why were those two coming together? So fascinating. So this is a white blood cell cancer, right? The myeloid cells are white blood cells, a branch of them anyway. And so to get chronic myelitis leukemia, you needed this genetic migration thing to happen. On one side of it is the BCR gene. And that gene is basically responsible for immunoglobulin kind of reshuffling in white blood cells. It's a very dynamic, very active gene in white blood cells. If they a very dynamic, very active gene in white blood cells. If they're going to be able to do their immunologic job and create the relevant kind of repertoire of foreign recognition, then the BCR gene needs to be active to facilitate that program.

Let me put it that way. So any case, the BCR gene is on one end of this migration event. It's not a doer in and of itself. It's just a very active gene locus that's just on, on, on in white blood cells. On the other end is the abel kinase. So abel kinase is a signaling molecule. It's inside of cells. It's not important in all cell types. It's important to a degree in white blood cells. That's, I think, a fair summary statement now looking back 20 years in retrospect with a lot more information. But this is a signaling molecule that does a lot of work inside of cells. It's a kinase, so it phosphorylates substrates. And when BCR-ABL, this very active regulating domain, is stitched onto the ABL kinase... BCR is stitched to ABL.

Yeah, that's correct. So it creates the BCR-ABL translocation or fusion. So you now have a new gene product of these two genetic components being stitched together that otherwise wouldn't have been. They're quite far apart from each other on chromosome 9 and 22. So in any case, when they come together, you crank up the expression of able kinase. So able kinase is normal. Able kinase. It's not mutated.

Yeah. It's just all of a sudden, instead of firing once every minute, it fires 40 times a minute. It's jacked up. It's an expression to preposterous degrees. You have an enormous amount of able kinase being made in these white blood cells because the BCRR locus is just being driven all the time in normal white blood cells. So now you've got able on the other end of that. Which is really aptly named. Abelson was the discoverer of it. But in this context, it's aptly named. It's very able. It's an able kinase that has become much more able.

Right. But unlike BRAF, which has this activating mutation sitting right in the middle of it, nucleotide substitution resulting in an amino acid substitution that alters its kinase function, this is just normal able. Yeah, it's just more on. Yeah. And HER2 amplification in breast cancer also, just there's more of it. And then they complex together and signal more.

So when we talk about mutation and genetic alteration, just understand that there's more of it and then they complex together and signal more. So when we talk about mutation and genetic alteration, just understand that there are these, there's amplification, there's point mutation, and there's translocation or fusion. These are the three canonical ways that you can have it. And do most of the fusions have this phenotype? So this is other fusion cancers outside of. Meaning do they have this phenotype of normal protein just doing more? Precisely, yeah. And kinases are the ones that have been discovered, described, and now drugged multiple times. So what's fascinating about now, this is a 2019-ish insight, or at least the past few

years, is these fusion or translocation, quote unquote, driven cancers, they tend to be genetically simple. Not all of them. quote unquote, driven cancers, they tend to be genetically simple. Not all of them. Point mutations happen in the sea of genetic complexity, melanoma being an example, but all BRAF mutations distribute across cancer types that are actually quite genetically complex. There's a lot of other genetic aberrations turning on and turning off other things. These fusion-driven cancers, they seem to get a lot of juice out of that one genetic alteration. So BCR-ABL was the initial example. But remember, it's chronic myelitis leukemia. It would kill patients

over five to seven years. And it was super genetically simple, at least at the level that one could make such comments in the 90s, which is when therapeutically attention started to be turned to this ABL kinase phenomenon. So it turned out that Sivagaygi ultimately subsumed into Novartis over serial acquisitions, had a kinase inhibitor program broadly for cardiovascular disease. I knew Sivagaygi from my father's academic cardiology pursuits. So they had these kinase inhibitors. They were pretty crude instruments, but in the mix, my understanding initially was all endothelial perforative cardiovascular disease was the kind of phenotypic screening, if you will, that was being done with the kinase inhibitor library at the time.

Again, this predates the cancer investigations. So they created this library, not massive, of kinase inhibitors. It's a small molecule tool compounds. So there's this guy, Brian Drucker at Dana-Farber in Boston at the time, who uncovers that now Novartis has this kinase inhibitor library and in it is a apparent able kinase inhibitor. Not perfectly selective for able kinase. Kinases exist in the hundreds. So about 600 or so kinases have been described in the family tree. They're highly related, but then there's some that are more distant cousins than others. And if you try to inhibit a kinase, it's pretty easy to pick up inhibitory activity against

another kinase because of their relatedness, their structural relatedness. So it turns out imatinib, the first able kinase inhibitor, was not just an able kinase inhibitor. Fortuitously, it was also a C-kit inhibitor, which we'll come back to because that's the gastrointestinal stromal tumor, dual purpose of that molecule. But any case, he wanted an able kinase inhibitor, which we'll come back to because that's the gastrointestinal stromal tumor, dual purpose of that molecule. But in any case, he wanted an able kinase inhibitor. The more perfect he could have had, the better, more selective and only targeting able. But back in these days, certainly in the nineties, it was a difficult sport to actually profile how promiscuous or selective a kinase inhibitor was. So it wasn't really known what its full selectivity spectrum was, but able kinase is what it was labeled as an inhibitor of. So it's been cataloged in many

papers, but just briefly put that basically Brian started this campaign to try to get Novartis to liberate this molecule that had been to a degree investigated in cardiovascular disease models, but to like kind of get it out of the company and have it actually made available experimentally initially in model systems, not even in humans yet. Any case, fast forward now. So the drug enters phase one clinical trials in cancer patients with knowledge that there's this cancer out there. And this is like mid nineties? No, no, no. This is now late 90s, and I'm about to

show up in fellowship in July of 2000. And it's 2000, 2001 that the ongoing phase one trial cleared the first few dose levels where somewhat homeopathic doses were given. Didn't have to go on for very long as a phase one study. Recruiting these patients, these patients who didn't need to be molecularly tested because you just knew by their diagnosis that they were at least 95% likely to have this alteration in those cells. And so it was in the midst of my first year of fellowship. Yeah, this is the phase one trial where there's efficacy. Yeah. First time ever that basically consecutive patients were responding to therapy in a phase one trial as the dose was still being escalated. So talk about aha moment.

I mean, you needed three patients, six patients, not a big phase three trial as the dose was still being escalated. So talk about aha moment. I mean, you needed three patients, six patients, not a big phase three trial to know that there was a transformational event happening. So that happened in the first year of my fellowship. And my naive talking points, I was saying, you know, this is the future of cancer. This is what we're going to do. This is it. This is our first AZT moment. Drugs working extremely reliably, killing lots of cancer cells, admittedly not eradicating all of them in most patients, but still there were cures even in the early days or at least durable, complete responses. So anyway, the point being that this was the big moment. The objection to that big moment relates to the comment I made a

little while ago, which is this is chronic myelitis leukemia. This is a genetically simple thing. This is barely cancer compared to pancreatic cancer. This is barely cancer compared to non-small cell lung cancer. Okay, fine. It worked here, but why on earth would you think this is going to work in real cancers? And again, let's make sure people understand why you're saying CML is barely cancer. You have a translocation fusion that does not even mutate the kinase involved. So is it safe to say that someone with CML doesn't actually contain true genetic mutation? That's fair. Stable phase CML, as it's called, which is this long period of time where people will have large numbers of these abnormal white blood cells circulating, but not impairing their health in any significant way. Stable phase CML

is this genetically simple thing. Given enough time to evolve, just like we talked about with the small solid tumor, give it enough time to evolve, it will pick up more alterations. And the rate at which alterations are picked up accelerates also. So evolution begins to happen in a more substantial way, leading to accelerated phase and then blast crisis and patients die of an acute leukemia-like death. So CML isn't quote-unquote real cancer in this objection-rendering frame here for a good long time, but it certainly becomes real cancer ultimately. So the New England Journal of Medicine publishes the back-to-back papers in 2001 now of the phase one clinical trial describing these heroic and quite reliably observed responses to single agent abel kinase

inhibition with a non-perfect abel kinase inhibitor in the form of imatinib. So this felt certainly like a big deal. The next paper in this back-to-back, same authors, were reporting on the activity of imatinib, the antitumor effects of imatinib in patients with accelerated phase and blast crisis CML. So same disease, now allowed to genetically evolve and become more complex and certainly to pick up additional mutations beyond this foundational translocation event. What happened in those patients? It wasn't even discussed. People for years were celebrating this CML, stable phase CML result, and never would you see a talk describing, well, what happened with the same drug now in a more genetically

complex environment where the same truncal as an original alteration existed, but now surrounded by these other partners that were clearly important because now you're transforming into a truly aggressive, life-threatening disease. You got responses. They weren't durable. They were transient. They lasted for months at best, weeks in some cases. So yeah, you could poke it with a stick, but it would just laugh its way right around within a very short time and patients would still succumb to their disease. So this is where the debate was. Okay, so you have CML in its stable phase,

where you get these kind of heroic, deep and durable responses. Okay. Map that out for me and the rest of cancer. Right. So you realize that CML is the exception. It's not the rule. Well, this is the argument, right? This was the argument that never again, are we going to find such genetically simple cancers where you can get deep and durable responses from a single agent targeted therapy? Now, again, I didn't feel so defeated by that argument in the sense that my talking point, even before we had the cancer equivalent of AZT, was, well, this isn't going to be about one drug. This is cocktails. Look, it took cocktails to wrestle HIV down. And that's a laughably simple organism compared to a human cell that's now been co-opted by the blueprint being widely opened.

So of course, it's going to take combinations. How high order a combination do we need? Well, that goes back to the building block argument. We still don't know. Any case, but we still need to find our individual AZT moments and hope that they would actually do something for an individual patient and not just serve as a biologic building block. So this was the subtext. Fast forward and just connect one dot, which is that, well, one thing that we have learned is that even in so-called solid tumors, so leaving aside the leukemias like chronic myelitis leukemia, even in solid tumors, you will find subsets of them that are driven by these translocation fusion events. And they tend to be genetically simple. And now

time and time again, that has proven to be a population sparsely distributed, if you will, across cancer types where you get deep and durable responses. That was the next big aha moment. So time matters, meaning? Evolution. Well, yes, but also like if you catch CML and treat it early enough, in theory, you're going to have a better response than waiting until the tail starts coming out of the dragon. That's right. So the compensation that a cancer cell will be able to leverage by having now these built-in accelerants or more disabled tumor suppressors, like the ability to adapt and work their way around with de novo resistance or

rapidly acquired resistance is absolutely a huge risk the longer you wait. That CML example, well, we've begun to map it out in quote-unquote common solid tumors. So in breast cancer, if you look at HER2, I was beating up HER2 for its not aha moment efficacy. This is trastuzumab, the first naked antibody. But modified forms of HER2-targeted therapies have come along since. These more armed antibodies, if you will, that definitely have greater effect. But even just take trastuzumab, the naked antibody, its ability to help a metastatic breast cancer patient live longer for a period of time, well cataloged, but measured in months, several months, let's say. Now you take that into the so-called adjuvant setting. So this is covert

metastatic disease. So for those who have heard enough jargon and had family members deal with cancer, they know of two situations where the surgeon says they got it all, but the medical oncologist is telling them, we're still worried. There's still some cancer cells around. We're too stupid to know if they're there or not. CAT scans can't tell us because they're too low resolution. We're not there yet in terms of actually measuring circulating tumor cells or circulating tumor DNA in a diagnostic and high resolution way. But we're just worried because we know that looking back a decade, if we had a thousand cancer patients like you, we know that half of them are going to show up with overt metastatic disease over the first few to several years of follow-up.

So you know a time that someone had microscopic metastatic disease after their surgery with curative intent. So what I'm getting at is now that's the adjuvant setting. So the possibility, but not certainty that microscopic metastatic disease exists, you give therapy in that situation, systemic therapy to seek and destroy microscopic deposits, that's so-called adjuvant therapy. So with that jargon stated, adjuvant use of HER2 antibody, this was the first example of this is why I'm giving it its due credit, cures patients, cures patients. You don't cure patients in the overt metastatic setting with HER2 antibody therapy. Like that's unheard of. So that was the first paralogue in a common cancer that kills lots of women, that this CML evolution concept.

And remind me what the numbers were, because we sort of take it for granted today. You take two groups of women that have her two new positive tumors that are NED, meaning surgically resected down to having no evidence of disease, as you described, half of them get a placebo, half of them get the antibody in 10 years. What percentage are alive in each group? Usually the way we think about it is like how many patients are saved, if you will, because it all depends on the level of risk of recurrence to start with. Yeah. So what's the AR and RR? Yeah, right, right. So whatever you start with, so it's depending on the trial, a third to a half of the recurrences that would have occurred don't happen

by the addition. This is, you're right to mention placebo, but by historical fact, in this case, everybody got chemo. Everybody gets the same. Yeah, chemo plus minus, if you will. So the addition of the HER2 antibody or not, and this is now many subsequent studies and other cancer types have been done to try to show the same kind of benefit of treating only microscopic or digital disease as opposed to overt metastatic disease. So a third to a half reduction in risk of relapse over long periods of time now and stably so in the case of HER2. We have lots of data. Do women take anti-HER2 new for life now in adjuvant or how many? It's five years? No, no, no. The hormonal therapy is the long duration therapy in the adjuvant setting.

So hormonally driven breast cancers, you're now complicating this, my attempt to make adjuvant therapy disease eradication sounds simple. H hormonally driven cancers like breast cancer and prostate cancer in the so-called adjuvant setting it is clear that the original data was a year of therapy then three years of therapy five years of therapy it's clear even that 10 years of therapy is better than five years of therapy in a population and hormonal therapy prevents relapse at least to a third to half standard analogous to HER2. But when you see an effect like that in series of clinical trials where longer durations of therapy to treat covert metastatic disease, longer is better than shorter, it tells you you're not eradicating in everybody, you're suppressing in some people. And that's the

story over and over again. And gastrointestinal stromal tumor, which was the first solid tumor, big targeted therapy success, where imatinib was being repurposed for the fact that it's a C-kit inhibitor, and C-kit is mutated in two-thirds of gastrointestinal stromal tumors. That drug first showed benefit in metastatic patients, overt metastatic patients. Then in a series of adjuvant trials, one year, three years, now ongoing therapy beyond that, incrementally better. Is there a reason to believe that some patients are being cured? Absolutely. But there's some patients where a disease is just being suppressed and maintained in a micrometastatic state from which they will not die, at least in the foreseeable future.

But this just goes to my point about, okay, is single-agent targeted therapy a tumor-clearing treatment for very many cancer patients, even when we use optimal next-generation early detection methodology? That is going to be realized in a real fraction of cancer patients. But we're still going to need combination regimens to dismantle tumors in their fully complex way. The BRAF example has already now played out. So melanoma, BRAF inhibitor monotherapy, improved survival to the tune of a nine-month improvement in overall survival, which in melanoma, which is median survival used to be six to nine months, or on average six to nine months. So like getting a bump like that. You're basically doubling the survival of patients with metastatic melanoma, but not curing. Right. That was a big deal. Interestingly, BRAF inhibitor monotherapy was tried in an adjuvant trial. Didn't meet its endpoint.

So it apparently numerically reduced risk of recurrence, but marginally so, and not enough to achieve statistical significance. So that trial was called negative. In parallel, I and others had been pushing hard in the metastatic setting to go from AZT to doublet. What was the first doublet HIV regimen? I'm blanking now, but in any case, a proteasome inhibitor. And so in any case, in melanoma, we were treating with BRF inhibitor monotherapy. We're seeing responses. Those

responses would last on average six months. This is an aggressive disease. Again, patients would typically die within six months in the untreated state. So patients would respond and there was response that would be maintained for a huge range of times, but the average was six months. We saw that basically the tumors were working their way right around the drug in the MAP kinase pathway. They were bypassing BRAF through CRAF most commonly. That was the easiest trick for them to use. They didn't need to develop mutations that resisted the drug itself, which is a theme in BCR-able CML and other oncogene-driven tumors that are treated effectively with targeted therapy, and fusion-driven cancers in particular. Remember those genetically simple tumors? A very, very common theme is they need to mutate the actual gene that's being targeted because

they need that thing back on. They don't have very many tools in the toolkit. They need that guy back on, and the only way they can evolve resistance is to basically repel the drug in the first place. Those are so-called gatekeeper mutations. So in BRAF mutant cancer, BRAF mutant melanoma, you don't see those mutations emerge because it's too easy for these cells to rewire their way past BRAF through CRAF. So we saw this happening in humans. So yes, in parallel and laboratory systems, but more importantly, we were seeing it in humans within the same year that we first documented responses in those patients, because we were biopsying them serially for research purposes, which was then thought to be a crazy concept, but now it's not so crazy.

In any case, we saw this bypass happening. We knew that there were available inhibitors of downstream MEK, M-E-K, the guy that BRAF turns on. Those drugs already existed. They weren't shown to be useful on their own yet anywhere in cancer. There were signs of life here and there in clinical trials. But MEK is right below BRAF and C-RAF. And we said, let's just put these two together, try to intercept this bypass. That worked. Like we went very quickly from BRAF inhibitor monotherapy to BRAF-MEC combination therapy, including overall survival improvements that were as big as the overall survival improvement, BRAF inhibitor monotherapy. I'm fast forwarding through my entire career here. Any case, BRAF-MEC combination in the adjuvant setting prevents relapse by 50% and patients

receive a urotherapy, stop treatment, and there's a persistent gap there in terms of cured patients. This is melanoma we're talking about. Melanoma that will work its way around BRAF inhibitor monotherapy in, on average, six months. You can wipe it out in the covert metastatic state, microscopic residual disease, aka adjuvant therapy, with that same regimen. So the point is there is some real kind of early detection, early treatment theme that is absolutely yet to be fully leveraged and realized because we're still working on the early detection technology, blood-based mostly, but it's coming. And then adjacent to that, even in some cases, when we find cancers very early,

they are already genetically complex. We have to have a toolkit that allows us to dismantle at more than one point. And that's its own long conversation. But the issue of adjacent to AZT, what does that armamentarium look like in terms of the next agents that we're dismantling? Because with HIV, we think of it by class of drug. You basically have a toolkit of drug classes. And it seems to me that you've done a very eloquent job explaining this. There are basically some fundamental pillars in growth and some fundamental pillars in protection. And when the day comes that we have a toolkit

that knows, okay, I've got these three things that can hit this pillar, three things that can hit that pillar, four things that hit this pillar, six things that hit this pillar, nothing that hits this pillar and two things that hits it. I mean, that's, you're in the golden zone when you can start stacking because that's what heart highly active antiretroviral therapy did. It basically put whatever three or four pillars together. And at that point, HIV was not cured, but it was chronic. You didn't have to die. You didn't have to get AIDS. We can't keep hitting the same pillar and expect that we're going to cure cancer.

So we got away with it in melanoma because we kept hitting the same pathway, got away with it by hitting it twice and improving outcomes and actually improving side effects, which is its own weird story, but really cool story biochemically. The bigger point, just hitting some of the talking points that we touched on before, is we need the activators of the immune system. We need the inhibitors of the activated oncogenes. We need the drugs that target these epigenetic regulators. We need the metabolic switch regulators, which are emerging, I would say, just as we speak, very early days.

Epigenetics and metabolism generally are what I point to to say that these are the pillars where the tools are coming, but it's early. And I generally make the point that if we just flesh out those toolboxes and we're lacking still, some famous gaps would be like understanding how to wrestle down telomerase. This kind of like is a clock that exists in cells that allows them

to basically measure their age. You see the science paper last week, it was the science paper about the, the astronaut Kelly's time in space, the year in space. I read a lay article summary of it, but yeah, go ahead. You know, it's interesting. So twin brother, right? So one, the only bring this up cause you mentioned telomerase. So I could be having this backwards. I think the telomeres of the astronaut that was in space elongated significantly during his year in space, but within three days back on Earth, completely reverted to normal, which of course just made me question the importance of telomere length.

It's an interesting point. So your pillars then, because I want to share with you my framework, which is purely a clinical framework. It's not a research framework. It's a, you're on the front lines, you're a primary care doctor, you're a patient. How do you think about cancer? Because while I think most patients, when you talk about the big diseases, most people are afraid of Alzheimer's disease above all else because of the phenotype. But when you think about probabilistically, most people are afraid of cancer because the likelihood of getting it is somewhere between a third and a half, depending on your gender. So you said epigenetics, metabolism,

immune. Would those be your three fundamental pillars of cancer? Yeah. I mean, growth factor receptors, which again are... What within them? That was the original pillar because those are the first discoveries made, frankly, in cancer biology and cell signaling. But these others are clearly the other major pillars of normal cell programs that have to be co-opted by cancer for cancer to achieve its goals. Yeah, so the epigenetic modulation, the immune stuff, the metabolic stuff, and of course, the growth factors. So I usually tell patients, I think cancer is is really hard Like atherosclerosis is inevitable, but we also know so much about it Not everything but we know enough about it and we have enough tools that look if you really want to be aggressive You can delay it so that you're not going to have your first heart attack till you're 100. That's doable

That's totally doable if you start early enough I'll save my soliloquy on Alzheimer's disease. But I say, look, cancer is the hardest one. And it's the one that I think most about in the sense of it's the one that I am least confident at our ability to reduce risk in. So I say, look, here's my take on it. Step one, try not to get cancer. Sounds like a dumb thing to say, but we know a handful of things that are increasing our

risk for cancer. So let's keep those to a cancer. Sounds like a dumb thing to say, but we know a handful of things that are increasing our risk for cancer. So let's keep those to a minimum. Luckily, most people have figured on that smoking is not a good idea, but right behind it is insulin resistance and obesity. And so there's something about that probably down. So if smoking was probably acting more on the mass genetic level, something about insulin resistance was acting on this growth sort of pathway. Okay. So we could talk about all the things we can do to not get cancer. Step two, which again, creates a lot of enemies, especially depending on which side of the Twitter sphere you live on is let's look for cancer early. If burden of disease matters, you can take the approach of women should never have a mammogram. Just if a lump shows up in your breast, go see your doctor,

but otherwise don't do anything is one end of the spectrum. And then you've got coconuts like me on the other end of the spectrum that say, no, I understand why you might come to that conclusion if you're trying to do it at a cost basis. And if you're only limiting yourself to mammography, which has such horrible sensitivity and specificity. But if at least theoretically, you could say, well, in a world where costs become less ridiculous, i.e. not in the United States, if you took it out of the equation and you were willing to layer mammography, which will always be important to catch a calcified lesion with diffusion weighted imaging MRI as an even superior technology to ultrasound coupled with molecular screening,

well, you can make the case that no woman should ever present with breast cancer. And in that situation, can we do better? And then you talk about looking at therapies that would go after multiple pillars simultaneously, not in serial, not waiting for one to fail and the other to go on. So that's my sort of Neanderthal approach to cancer. How would you make that more robust? Okay. So what we're missing is still components of the toolbox to be able to actually knock out pillars. So that's, I often say we still need to diversify our toolbox. Then it's the issue of marrying diagnostics with therapeutics. So understanding the assembly process of cancer in a patient-specific way and being able to deploy those

therapies. That is an emerging hard task. I spend a lot of my academic time railing against the impediments that keep us from pushing drugs together in supervised settings, both experimentally and clinically in clinical trials. So this idea of getting to following the HIV example, we are chronically facing headwind in terms of getting there. Is that because HIV killed patients so much quicker and there was more desperation that clinicians, IRBs were more willing to move quickly to stacked therapies? Yeah, we have all the same regulations. The HIV advocates created... It was the advocacy. Yeah, they created regulations to cover life-threatening disease,

and cancer is captured right in that. We have an amazing forward-thinking regulatory environment in the United States and increasingly in Europe. Because of the lead blocking that was done by the HIV advocacy community, we have the same benefits. So the heavy lifting on that front was done in the 80s and early 90s. And I've spent tons of time exploring whether there are remaining impediments there, talking with FDA leadership in particular. And I usually quickly sum up to say they are on our side. They are our friends. They have self-organized in a way that actually will be the accelerator, not decelerator progress.

The problem, if I were to put a finger on it, is the way in which way that actually will be the accelerator, not decelerator progress. The problem, if I were to put a finger on it, is the way in which companies that decided they could see a business model in HIV and basically decided they were going to pursue it could create the toolbox within their one company. Had it not been for that, we would not have seen doublet and triplet therapy. And is that purely a simplicity of therapy and therefore an economic issue? Precisely. And simplicity of the organism that you're talking about. That's what I mean. Yes. It's simplicity of the opponent. That's right. The number of enzymes that the thing has in its genome, you could then

postulate as potential targets, massively smaller. And so within one umbrella of one company, you could see combination therapies being- Right. So even though Merck or Pfizer could have a program under each pillar, that's typically not the way it goes, is it? Here's how I generally draw up the math. So 60% of drugs coming in the cancer pipeline now come from small biotech companies. It used to be that big pharma was the driver. And the phrase I often use is that big pharma outsourced its R&D to risk-taking, venture-backed, highly specialized small biotech companies, not just in cancer, but here I'm sticking with cancer. So you've got this distribution of where drugs are coming from that is a huge swath of different firms, many of which have a single asset in the small biotech

space. And at most they get to have two or three. What's the sweet spot for big pharma is between phase two and phase three or between phase one and phase two, if you exclude the big aha moments. Yeah. Okay. So if it's an aha moment, then it's phase two. That's the acquisition moment. And if it's not, then it's randomized phase two slash phase three. Optimal moment, as you said, kind of where's enough risk been taken off the table and where now you've got a commercialization opportunity, which is what big pharma is for us in oncology, at least. Yes, there's still innovation and incubation, new therapies coming out of big pharma. But as I said, it's shrunk down to a small component. The basic science, as you well know, across all of public-private domain is in the public sector, right?

The basic science, the stuff where you can't guarantee any kind of return in terms of when you're going to get an insight that you could turn into a potential therapy. So you've got this fantastic chaos of publicly funded biomedical research, the world's greatest bio. I was just about to say, by scale, when you look at the public domain, everything from most of it, of course, being NIH, but also Howard Hughes and others, what percentage of the world's pure exploratory science is funded in the United States? 90%. It's that much of an advantage. Yeah. It's narrowing in Europe a bit.

With now central investment in cancer research in Europe, that number is dropping percent by percent. Truthfully, if you said 50, I would have still thought that was impressive. No, no, no. If half the world's basic exploratory research was happening. It's where the money is. The public investment in research and then add the private. I'm adding the philanthropic on top of that, but yes.

Yeah. Well, we live in a philanthropic environment that's not known in much of the world. So that is a meaningful additional layer. So no, a huge, huge, huge engine here is the public domain. Those discoveries then are outlicensed to small firms over large firms by a huge margin. Of course, I here live in one of the, well, not one of, the world's biggest biomedical research engine vis-a-vis taking those discoveries into small firms and the Bay Area for sure, and New York and San Diego are the kind of other

major pillars of that. But so you have these hubs of activity of taking new discoveries, some of which come from outside the United States even, but then are incubated into companies. What I'm describing here is this very dynamic, very exciting, very purpose-driven, expertise-heavy biotech sector, which is great for so many reasons, but I'm bringing it up as a complaint, even though I personally have benefited from the ability to step into entrepreneurial roles and co-found companies and so on and so forth, and been enormously gratifying for so many reasons. I registered as a complaint because it's distributed our toolbox so widely, and we live in a world right now where 0.37 of rational combinations of two cancer therapeutics that are still in investigational territory are finding each other in clinical trials.

I published a paper on this topic a year and a half ago. It is a terrible sampling mingling rate, terrible. So we make new discoveries all the time in the academic domain that would suggest a new combination. You've got patients dying every day of that addressable cancer by molecular subtype or whatever. The likelihood that you're going to be able to launch a clinical trial to marry those two drugs when they exist in two firms is that small. That is a terrible problem. HIV didn't have that problem. But because of the complexity of human cells and therefore human cancer cells, the toolbox is being chaotically distributed. We need a way to change that. And we need a way for drugs to be able to be married in life-threatening cancer in a rapid, rapid fashion. So it's not an inertia problem in the culture. It's not doctors. It's

not patients. It's not academic medical centers. It's not the regulatory environment. It's not. And it's a shame because some of those are a heck of a lot easier to solve. You'd think. This is the least rocket science thing that I've put my shoulder into the past number of years now. Novel, novel cancer therapeutic investigation. But it's the hardest to change. And to me, there's an obviousness in terms of focusing on this problem.

But the obviousness in the entire ecosystem in terms of actually getting alignment and incentives aligned to allow this dabbling to happen, it is a major, major impediment. And I've been making the point that I think we need quadruplet therapy to dismantle most complex cancers if early detection is only going to get us so far. And ideally across four pillars. Yes, exactly. And different ones, right? So going back to get us so far. And ideally across four pillars. Yes, exactly. And different ones, right? So going back to the PCP3. You have a huge combinator.

Right. You might want to always be targeting tumor suppressors. Yeah, sure. But that's not one drug. That's right. That's up and down the chain. Right. And unique to certain patients' tumors.

Now on the tumor suppressor side, does CRISPR offer any role? Because if you fix a tumor suppressor gene, that seems more beneficial than just fixing oncogene. This is gene therapy. You need to be able to deliver that to every last cancer cell. And how in the world do we do that? Is there a virus that can do this? No, no, not currently.

And I, in the beginning of my career, because if I've communicated nothing in talking with you, I am an optimist. The beginning of my career, I absolutely thought like this is, on one hand, we have these things that we need to inhibit. And on the other hand, thank God we're going to have gene therapy. 20 years later, we still don't have gene therapy. We have gene therapy that can correct. If you need only a little bit. We're at Penn when Jesse. I got there right after. Okay. Yeah. So I was still to Brigham at the time when I was postulating that gene therapy was going to help us on the tumor suppressor side. And yet friends of mine who were in the lab doing work on genetic delivery methods were saying,

no, no, we're not there. These adenoviruses are getting wiped out. You can't get persistent expression. Hemophilia then to a degree now was kind of paradigm case where people were saying, we just need to get these clotting factors expressed to a little degree in a small fraction of cells and we'll be okay. As people were trying to just climb that hill, I was like, well, that's not the cancer hill. The cancer hill is every single cell widely distributed. And some of these cells are dormant. These micromats, they've lodged in distant sites and they are truly quiescent dormant cells. How are you going to get integration into that cell? So it's a major, major problem. So I don't see that trick coming in the foreseeable future. So I don't focus on it. I do think we can understand the pillars up and down, as you said, and knock them out in ways that potentially at least turn off what's turned on as a consequence. I mean, this is a thing about tumors of breast genes that are eliminated, is that you can always find a downstream thing that's turned on as a consequence. So the issue is, can you find that point of drug ability intervention to counter that? So that's at least until I retire, I think that's

going to be the relevant approach. You've alluded to it already, but are you pretty bullish on liquid biopsies? For sure. There's several reasons why. The early detection piece, I think we've touched a little bit on. Let's tell folks what they are. I use the term from time to time. Right. So tumor cells, a primary tumor with no, let's go with the notion that we can have knowledge that there is no microscopic metastatic disease. It's just a primary tumor. Right. You have a tumor in your colon. You have an adenocarcinoma in your colon, and we know that it's nowhere else. And that thing will shed its genetic contents, DNA and RNA, which mutated genes will have their mutated RNA versions. You have mutated DNA and RNA

kind of detection opportunities, if you will. So DNA is shed, we think, from lots of cell types, but definitely cancer cells seem to disproportionately shed their DNA, which is chewed up a bit as it circulates in the blood, but you can find it. And with higher and higher resolution technologies, if you find a single copy even and can amplify that up and detect it as a signal, since we know what the genetic map is of all cancer, we can have those probes reasonably well in hand. And a lot of acceleration has happened in this space the past just few years now. I'll come back to my complaint on the impediment side when it comes to reimbursement of diagnostic tests because that's the problem I think we face there in reality. But from a public good perspective and from a science perspective. I mean, I'm just curious right now from a purely, like I'm thinking about this through the lens of cancer screening at the population level. And again, I'm always trying to make the problem

simpler by taking away one constraint, which is cost. Because in the short term, I think you have to start, if you try to solve this problem at a quality adjusted life year perspective, one, you're inserting your morality into the discussion. And two, I don't know what the number is and it's too hard. So let's make the problem simpler. All we're doing is trying to reduce the risk of physical harm to a patient and psychological harm through false positives. If you could layer liquid biopsy on top of diffusion weighted imaging, MRI, the best colonoscopy, the best mammography, boom, boom, boom, boom, boom, boom, boom. I mean, you can theoretically construct a point where you can catch every cancer prior to its clinical presentation. Yeah.

Let's just go with breast, colon, prostate, and lungs since that's 80% of solid tumor cancer deaths. So that would be a good goal just to go after those. So the challenges are, so again, the DNA is shed. Do we have a sense of how big a tumor needs to be to even start shedding? It has not been well mapped out, but certainly less than a centimeter. And this, you mentioned centimeter before, radiographically findable and so on, nodule. So if you go map out cure rates with surgery alone across common cancers, breast, colon, prostate, and lung at centimeter. Right. At centimeter below.

Yeah. The exceptions are few. I mean, pancreatic would still be one of the few where even sub-centimeter, your odds of survival are less than 50-50. Melanoma happens to be measured in literally one millimeter increments. So huge metastatic potential. But in any case, we have other strategies for that superficial tumor to find it early. But in any case, so coming back to your point.

I see your point, which is if you could decide no one ever shows up with a tumor bigger than one centimeter, potentially doubled cancer survival, right? So those guys are definitely shedding. So it should be detectable. If we need to use microvesicles or exosomes, which have RNA and some DNA in them as a way of being able to find scarce entities, these mutated gene products that are now, in this case, in the case of exosomes, why they're being transmitted around the body, we don't know, but it happens. Not just tumors, of course, normal cells do this too. So circulating tumor DNA, exosome or microvesicle packages of nucleotides. These opportunities for detection, as well as

circulating tumor cells, but circulating tumor cells are based on available technologies. They're the hardest to find in a patient who has a one centimeter tumor nodule, using that as a threshold. So already it's in sight that we're going to have a high resolution methods for shed DNA and probably same for exosomes and circulating tumor cells, I think could get there. The issue, to come back to your framing here of like false positives and anxiety provoking and so on, remember P53 mutations, 50% of cancer. Finding a P53 mutation in blood, what does that tell you? A, you might have cancer, you may not have cancer. And where is it? What part of the body is it coming from? Well, P53, 50% of cancer. It could be virtually anywhere. Yeah. So how much of the effort in the liquid biopsy is going to be histology specific?

Exactly. This is where circulating tumor cells would be the favored approach. The DNA will not offer tissue specificity. You can get the whole fingerprint out of a circulating tumor cell and know exactly what the entity is that you're hunting for now in terms of organ type. And so you just survey that one organ with every imaging methodology yet to come. So there's reason to be hopeful there going from CTCs forward. What's really cool in the circulating tumor DNA and exosomal RNA field is lineage mapping. So it turns out basically that the genetic blueprint, when it's folded up in a colorectal villus cell of the colon, the epigenetic alterations that occur in that

cell are characteristic. So you can fingerprint cell of origin by looking at epigenetic marks. This is a realization that's now being ported into the blood detection world so that you can actually map where did that fragment of DNA or RNA come from. So this is work in progress as we speak. There's an ongoing collaboration between our group and the Broad Institute at MIT on this topic, but I know of other groups who are in this space. So there's a convergence of sort of cell of origin fingerprinting with genetic detection methodology that you could readily see how we could get there

in the foreseeable future. This idea of being able to say, okay, our imaging still isn't picking it up, but we know that you've got a breast cancer brewing. And now. And in some cancers, for example, if you took a woman that was high risk to begin with, and now you had DNA proof that she had cancer, I suspect there are some women who would actually just say without additional imaging, I might be willing to just undergo a mastectomy or a guy would say, look, I'm willing to undergo a prostatectomy or whatever. Now it gets harder with lung cancer. You can't have just bilateral lobectomies all day long or pancreatic even, but that's a step in the right direction because as you said, maybe at that point we could justify even at the societal level, because certainly at the

individual level, you'll do anything, but at the societal level, we'd say, look, once you have that DNA test that points to that tissue, we're going all out on scrutinizing the tissue. And your first instinct is to think down a potential upcoming surgical path. If not, if you can't see it now, you don't know where to cut, but eventually you will. But I'm actually, as a medical oncologist, leaping to the systemic therapy concept. Can we motivate an immune response against that thing when we know enough about its genetic fingerprint or an oncogene targeted therapy and monitor the response using the same method, right? So when you were talking about blood biopsy, a huge near-term opportunity is to use it as a therapeutic monitoring tool to understand,

can you actually get people down to a minimal residual disease, no detectable evidence anymore by this blood method? So yes, it's an early detection tool, but it's also a therapeutic monitoring tool. So you can take a patient, you don't know where their breast cancer is, but you don't wait for it to emerge. You attack it when it's still genetically simple and monitor that effect in blood. So you know when to stop treatment or you know when treatment's not proving effective and switch gears to something else because you've got a toolbox with different regimens in it. I want to switch gears for a minute. There's so many just sort of cancer questions that I get asked all the time that I don't know the answer to. So I have at least two patients who I guess somewhat against my recommendation are adamant that stem cells,

intravenous stem cell therapy has played an enormous role in the improvement of their health. One patient in particular, there's no denying that his symptoms improved dramatically with IV stem cell therapy. And I don't want to represent that I have the hubris to suggest that it's not working. I just don't know. My bigger concern, because putting the cost aside and the immediate risk, like infections and sort of risks of the therapy, which are non-trivial. Of course, the risk on the other side, which is it's too successful in a sense, and those stem cells acquire a life of their own. So is this something you spent much time thinking about? I've thought about it. I

just think that if they're wild type stem cells, I think they'll follow the rules. So this whole discussion has been about cells that basically, not through anthropomorphic spiritual means but by random random genetic alteration basically are able to not follow the rules i mean this is this revolution that happens inside of our bodies that is cancer it's actually i usually use the term evolution this is this is individual cells following the preservation and success organismal success instincts that allowed us to crawl out of the swamp in the first place and become the complex organisms that we are, this drive to continue evolving for selfish purpose. So using that mindset to come back to your question, I think a truly wild type stem cell

will find its home and find its niche and its proper influences and behave accordingly is my assumption. Unless it were to become non-wild type through external manipulation outside the body, when it's potentially fragile and capable of picking up aberrations that aren't corrected. But stem cells are, they are notably hardy cells that can survive insults remarkably well and correct. So a cell that survives a genetic insult, a stem cell is particularly capable of detecting the damage, repairing the damage, taking its sweet time in doing so, and not spawning daughter cells until it's got its house back in order.

So its p53 detection program and DNA repair machinery is particularly robust. So this is why when people talk about cancer stem cells, notably, which no one would want those, cancer stem cells are thought to be kind of the worst of the worst. They're these primordial cells in the cancer cell population within a given tumor that have found their way back in development towards a stem cell and in doing so have adopted these really hardy skills, survival skills. No, they can't proliferate and divide very quickly, so they don't have that, but they can survive almost anything. Whereas the avant-garde, highly proliferative, very dynamic population that will multiply and actually be the life-threatening

leading edge of a cancer, those things are more vulnerable. So actually, if you look at what chemotherapy has done for us, it's fairly conventional chemotherapy. It's fairly clear that actually what it can do is it can prune this highly proliferative avant-garde population, leaving behind this more quote-unquote stem cell-like pool. And there's a whole field, it's a contentious field to a degree in cancer biology slash therapeutics of how much true stem cell biology really exists there. But you brought it up more from the perspective of whether stem cells themselves could go rogue. And I would say, unless they're perturbed in some significant and

ultimately genetic way, I don't see how. Now let's talk about another fundamental cancer question that serves no real purpose other than unless there's some clinical application of prevention, I suppose. It's impossible to deny the age-related association between age and cancer. Certainly kids can get cancer, but for the most part, cancer rates rise monotonically until the ninth decade or so. I mean, there's a bimodal distribution because you've got the childhood cancers. If you're 50 versus 60 versus 70, you leapfrog up in risk, right? Almost exponentially, or at least quadratically. It's not just linear. Consider two hypotheses. One is, as we get older, our genome is more susceptible to injury. Consider three. Two, as we get older and we've accumulated more of these, the probability that they can start

to layer and stack, and you get the phenotype that's not advantaged. Three, the immune system loses some of its steam and therefore the radar window in which you can detect cancer narrows basically, or the ability to detect all of the above, one of the above. All of the above. You've just described very nicely what I call the inevitability of cancer. We've got too many stochastic events accumulating and surveillance systems that are breaking down. DNA damage repair and immunologic. Those are the two fundamental, most important components. And if you're allowed to go one log shift in mutation burden per cell and the immune system not see it and not clear it. That's it. I mean, there's no human. There's no immune system that's going to. That's going to overcome that.

So when I say inevitability, you connect the dots in terms of the per decade acceleration and appearance of cancers across the population. And I oftentimes say, if we all live to 130, we all have a cancer, quote unquote, real cancer. Let's not get hung up on benign growths that aren't cancerous. The definition of cancer for a totally lay person who doesn't think about cancer much is ability to travel and actually wreak havoc and kill. Yes, glioblastoma kills in its local site, but benign tumors, which are almost cancers, yes, those happen broadly across the population. There's autopsy studies that show at least 50% of people die with at least a benign tumor. So almost getting there, sure, that happens already, but I'm talking about fully getting there, a full-blown and will be eventually life-threatening cancer. It's interesting, actuarially, by your 10th decade, your risk of cancer starts to go down.

Although, and I discuss this with my patients a lot, my explanation for that is that atherosclerosis ratchets up faster than cancer. And it's not that cancer is going down. It's that heart disease is dominating. And that's my, I say the same thing to patients that you do, which is whenever I get asked these questions that frankly kind of annoy me, which is like, aren't we just going to figure out a way to all live to be 200 one day? And I'm sort of like, no, what are you talking about? You have to figure out a way to prevent age-related disease. And yes, there's lots of cool ideas. And oh, what if you could just maintain telomere length is one I love hearing. And it's like, that's totally irrelevant because even if there were some benefit that came from that, you have to thwart atherosclerosis

and cancer. Yeah. You don't want a proto-cancer cell to be getting more telomere. Yeah. Yeah. Not even with Stamina. Going back to your stem cell comment, that's not a fix-all by any stretch. No, you're right. These are intersecting risk issues. So you're right that this competing risk issue makes it look as though if you make it long enough and you don't have cancer, then you're just not cancer prone. It's a bad problem to have when your risk of atherosclerosis is so dominant over your cancer risk. Now, one last thing I want to talk about is melanoma. And again, I don't actually know, I haven't written anything you've read on the topic we're about to discuss. So feel free to just dismiss it out of hand and say, I don't pay attention to that

literature at all. But have you been following any of the vitamin D melanoma sun exposure discussion lately? Yeah, sure. Okay, so I'll do my best to give a relatively brief synopsis and then feel free to just correct it because I'm pretty sure I'm bastardizing it. There's not a huge body of dissent to the notion that sun exposure increases the risk of melanoma. We know that... Not linear, but there's no question that there's an association there. Okay. So we won't call it, it's not an axiomatic statement, but it's the evidence that sun exposure and melanoma are associated in a causal way from sun to melanoma is strong. Okay. We also know that sun exposure increases the de novo synthesis of vitamin D in the human body. We know that from an association perspective, higher levels of vitamin D port with good things happening and low levels

of vitamin D port with bad things happening. This has led people to suggest that we should be supplementing with vitamin D because yes, you can get it by being out in the sun, but the risk of melanoma is going up, but we can just take it. It's a fat soluble vitamin. It's easy to administer. You can clearly achieve levels in the plasma that mirror that of the sun that should solve the problems. So many doctors, myself included, have historically normalized patients' vitamin D levels. Now, again, there's a whole spectrum in there. There's a bunch of weirdos that think you have to have super normal levels, but most of us walk around thinking, God, if somebody shows up and their vitamin D level is 20, we want it to be 40 or 50 or 60. The problem is these clinical trials, these pesky little things, keep showing up demonstrating that

supplemental vitamin D doesn't really seem to help that much. And I've scrutinized many of these trials and I can poke holes in all of them, but the body of evidence is becoming hard to ignore. So any one of these trials, I can say, look, they didn't use enough vitamin D or they didn't look long enough, or they didn't have the right patient population or, but when you have, I don't know what X is, but when you have X studies that are basically all saying the same thing, which is give everybody vitamin have, I don't know what X is, but when you have X studies that are basically all saying the same thing, which is give everybody vitamin D, it doesn't seem to matter. Now there's exceptions. You know, JAMA had a paper a week ago about supplemental vitamin D in patients with colon cancer, and it actually seemed to be a legitimate benefit. I'd love to hear your thoughts

on that. Where did this leave us all? This left us all, I don't know, for many of us about six months ago, there was a huge blitzkrieg of just nonstop information being put out about this that came to the suggestion as follows. The vitamin D that you take supplementally ain't fixing the problem. The vitamin D that's getting fixed in the sun is a proxy for things that are happening good in the sun. So it's sort of like saying gray hair is a proxy of aging, gray hair is a proxy of aging. Dying your hair black or blonde isn't fixing your aging. So get out in the sun. And oh, by the way, yes, your risk of melanoma will go up slightly. We're not denying that, but it goes up at one eighth, I believe is the number, your rate of decline of all of these other cardiometabolic diseases. So should we or should we not take

vitamin D? Question one. Or more importantly, I think for you, question two, given that you're one of the world's experts on melanoma, would you advocate we spend more time in the sun as a way to get our vitamin D? No, I don't go that far. Recognizing all of the cross currents in data, I thought where you were going to finish up, which is what you just said to say, exercise, exercise, and yet again, exercise. Okay. Are there people currently who exercise a ton, get a lot of cardiovascular benefit from that and do all that indoors? Yeah, that exists. So shouldn't we be able to pick that up in the data? No, I don't think this is a classic example of a confounder. I don't think that's extricated from the data. What I'm hearing you say is you think that the huge confounder is all these people outside

are exercising. That's what's been giving them the benefit. It's not the sun per se or the vitamin D per se. I'm going with the vitamin D being beneficial. I'm going to come back to a reinforcing element of that argument, at least as I see it in scientific evidence. What I'm getting at is that the most powerful benefit, you said good things are happening in the sun, or I think I'm paraphrasing what you said. And what I'm saying is that good thing

that's happening is exercise. I face this with my patients, melanoma survivors all the time. I love to- Ride my bike. Yeah. I'm a swimmer. I'm a runner. This is what I love to do. Is that okay? I've had a melanoma diagnosis. I have a 10% lifelong risk of what I love to do. Is that okay? I've had a melanoma diagnosis. I have a 10% lifelong risk of developing a new primary melanoma. So you, Dr. Flaherty, have told me I want to minimize that, but this is how I get my exercise. This is the conversation we have. I say, I get it. If I can talk you into a more sun safe version of exercise as an early morning slash evening running, swimming, tennis, I'm going to try to talk you

into that. Stay out of the sun in the middle of the day when now you're pursuing the cardiovascular benefit of exercise, you're taking on more vitamin D that you need, and you're taking on an inordinate risk in terms of the skin cancer risk. Obviously, other skin cancers are more common than melanoma, but not as life-threatening. So we usually frame this discussion around global skin cancer risk, where it's more linear with squamous cell and basal cell, the relationship between sun exposure. In melanoma, it's not as linear, but it's clearly causally related. So I synthesize all of the available evidence to say there's confounders in the behaviors that relate to sun exposure.

Vitamin D is still, I think, there's enough strength to say vitamin D. There's obviously strong associations, which is where you were starting with. I mean, the epidemiology regarding vitamin D levels and risk, colorectal cancer was one of the first to come, but then other cancers undeniably related to low vitamin D levels. So I think there is a causal relationship. I think you want to surf higher up in the vitamin D curve. The issue is how you get there. My synthesis is you exercise.

And if your exercise means that you get a low enough UV exposure that you need supplementation, then supplement. And until proven otherwise, it's those two factors that are why pure vitamin C supplementation alone is never going to do it in a population where you're not controlling for their exercise. Now, you're dealing with a highly motivated population, I think, in general. So they're inclined to be doing positive health behaviors. So they're probably already tackling the exercise piece. When you look at these studies, you're looking at a different population of people, in my

view. So let me just throw one little bit of science at you. It's a Nature paper published by my very close colleague at Mass General, David Fisher, who's one of the preeminent melanoma biologists in the field. So he came across this link in terms of the addiction potential of sun exposure. And it comes from the fact that melanocortin, which is the, if you will, the growth factor for melanocytes in terms of their daily function, as well as their development, comes from propiomelanocortin produced in the anterior pituitary. And that basically a

component of that gene product or this hormone is it's the pro hormone is cleaved into its hormones is endorphin. Endorphin is produced and released in addition to melanocortin at equal stoichiometric quantities. So it was that simple bit of endocrinology that led him to wonder, is there something about sun seeking behavior that's wired into us to try to get us to go out and get vitamin D exposure? You have to go back to evolutionary pressure times. Like, was there a reason why human beings would rather have not gone out and exposed themselves to sun because predatory risk, presumably? So that's a cute argument, but the wiring is very clear.

You can show that mice will basically prefer sun exposure, will go through narcotic-like withdrawal when you deprive them of their sun exposure. So it's meeting the criteria of addiction the way we would see it with cocaine, for example, in a mouse. Exactly. So it's of lower grade to a degree, but it's anyway, this fascinating initial paper in Nature and a couple of follow-on papers since then that kind of reinforces this kind of circuit. This idea that basically this is even in a lower species like mice, you can even detect this sun-seeking behavior that humans presumably have as well toward the end of getting vitamin D. So here's an argument to say, well, we're engineered to get out in the sun and there must be benefits from it. And the issue I think

that you posed is how much of the benefit is vitamin D? Then the shakiness of that argument is that, well, you supplement vitamin D, you don't seem to get all of the benefit one would think. Anyway, what I'm getting at is that, no, no, I think it's, this is a behavior that is maladapted for those who are going to live to be 60, 70, 80, a hundred years old. Not maladaptive for people who are going to live to be 30 and die, 80, 100 years old. Not maladaptive for people who are going to live to be 30 and die from predatory death or whatever the issue back in evolution. Yeah, evolution would have placed absolutely zero pressure on preventing you from getting melanoma.

That's right. So from a thought experiment perspective, if you could exercise indoors, never see the sunlight except through your window and supplement vitamin D, do you think you are doing as well health-wise as someone who does not supplement vitamin D, exercises outdoors, and attains the same vitamin D level? That's my hypothesis.

That's your hypothesis. Those are the same. I look at all available evidence in each study as it comes out, and I take that. I have that longstanding hypothesis. I put that filter on on and I say- Does this study contradict that hypothesis? So the idea that there's some other magical component of UV exposure, presumably UV being, that basically that there's some other magical property, I'd say we lack the evidence to support that. So I guess last thing I want to ask you about, because in many ways this interview, Keith, has been great because I think there are tons of scientists, scientists in training that I know enjoy this podcast. And I think you've offered incredible advice to people across different

levels of that spectrum. In particular, those people reaching out who are MDA PhD programs, and they're trying to straddle, how do I balance research and clinical work? And though you are an MD, not an MD PhD, you're from a functional standpoint, you are an MD, not an MD, PhD, you're from a functional standpoint, you are an MD, PhD. You are a clinician who predominantly does research. I want to ask you another question along that thread is you also do something that a lot of people haven't figured out how to do. And I'm curious as to what you've learned along the way, which is you have a very rigorous academic, completely standalone credentialed existence. And at the same time, you really understand industry.

You've been a huge part of industry and you seem to run these two parallel tracks that virtually, I don't want to say nobody, but most people really struggle to live on both sides of that. They usually tend to be very good at one and kind of mediocre at the other. I would add to that. I think people are cautious to believe that it would be a good idea to do it, that there'd be synergy in trying to live on both sides. That's been the lesson I've learned over the past, let's say, six years anyway in earnest,

which dates back to when I co-founded my first company of a series now of five and this year working on a couple more. Is that because of what you said at the outset, which is you were immediately focused on translational stuff? And if you were focused on basic science, for example, that synergy is a lot harder. I think that's right. Is it because of where the intersection you sit? I mean, I should back up a step and say that you can't do the work that I do and not interact with industry. So my entire career, the drugs come from industry. We do not live in a world yet where academic entities or the National Institutes of Health produce investigational agents, take them through their measures, and then make them widely available. That could happen. Actually,

there's a part of me that has pushed and advocated for that day to come because I think it would help bend the cost curve in a major way. But park that one for a moment. That hasn't been the world I've operated in. I depend on pharma, which means big companies, and biotechs to be aligned partners, at least for much of the time that we work together. The misalignment totally comes. And when it comes, we shake hands and part company. But my world has revolved around the fact that therapies come from companies proto therapies and then true therapies diagnostics kind of come from us and diagnostics are 50 of the equation they're woefully undervalued yet a lot of our research and nih funded research is about quote-unquote biomarkers that are in their best

form going to become diagnostics hey i mean this is the world's worst industry, right? I get that. But that's the point. But you can't direct a patient to therapy and use the phrase precision medicine. Without pairing it with the best diagnostic. So this isn't about diagnosing colon cancer. This is about diagnosing the molecular type and what its therapeutic vulnerabilities are going to be.

And that could be ex vivo functional diagnostics, not just static diagnostics. Shouldn't that just be absorbed into the therapeutic world? Right. Not just the cost borne by the therapeutic world, but also the development and deployment as well. And that's where it works. Companion diagnostics, quote unquote, are the success examples. It will still be the case that that therapy developing company marketed diagnostic and

therapeutic world will make 10 cents off the diagnostic, a billion dollars off the therapeutic. But if that's what it took to get there, then they will do it. They will also give the test away rather than bothering with the 10 cents. They will say, well, we readily recognize that we can't protect this diagnostic space. Yes, we have IP in this very specific diagnostic method, but we're going to get undercut by 10 to 100 others who are just going to come in and compete us. That's fine because we still own the therapy. And especially in a regulated environment, if certain companion diagnostics only link to that therapy, then the therapy developer still benefits. The problem that I faced in my career, this is now taking a little bit of a detour from your first question, but I'm

going to come back to it. The problem that I face as an academic is the issue of alignment slash misalignment around diagnostic therapy pairs. If you get to market in a broad population that is not biomarker selected and you can get there, you know you're treating some patients who aren't getting benefit from therapy. You've seen it in phase one slash two. You're still seeing it in phase three, but you're having enough of effect and enough of a subpopulation that you're able to drive a result in an unselected population. If you can do that, that remains in the current environment the best version of success there is. It decreases the degree of difficulty in terms of having two moving parts in your development plan, both a diagnostic

and a therapeutic, and you get the broadest population. Admittedly, patients who aren't getting benefit from therapy aren't going to make a lot of money for you because in a cancer context, they're going to get two months of treatment and stop. But still, broad population, broad use. A clinician doesn't have to think about doing more testing than they've already done. They just give this colon cancer patient the EGFR antibody, go back to the mid-2000s when that was the reality. A light bulb went off over hundreds of people's heads saying downstream of the epidermal growth factor receptor is RAS. And in colorectal cancer, RAS is mutated in a substantial fraction of patients. I bet that if you have a RAS mutation

downstream of the receptor, that tumor is not going to care about having the receptor blocked with the antibody. Brief run through the lab confirmed that hypothesis. An attempt then to carve out the RAS mutant population from an approved epidermal growth factor receptor antibody was a ground war that took years and years. The number of constituents, first the drug developer themselves and regulators joining them, who stood in the way of the most obvious scientific hypothesis I've ever seen in my academic career, it was terrible. So this is what I'm getting at misalignment is that basically if you do this too late and you're now carving out populations from an approved therapy disaster, because then you're relying on the diagnostic to be the, the tool,

the business incentive generating tool to carve that population out. And it doesn't exist. Now, if we had single payer healthcare and we had one ecosystem of constituents talking about this, we could talk about the savings and not having patients get ineffective therapy, and we could align on who takes ownership and responsibility, but that's not the world we live in. So in the meantime, it's a mad panic as an academic to try to translate the science to medicine with a diagnostic and therapeutic pair prospectively. So you get there at the finish line with a heroically effective therapy that's benefiting 80 plus percent of patients. You're always going to be wrong in some fraction, let's say, but you're almost nailing it in terms of assigning patient

in a truly precision medicine way. If you can do it prospectively, which is a mad panic because cancer drug development has moved more quickly in recent years, you've got to now develop that diagnostic, show that your biomarker positive, biomarker negative population do and don't benefit to the satisfaction of FDA in time to then have that diagnostic locked down, ready to roll with its approval supporting data set. So this is a long-winded way of saying that I've traveled this path enough times as a collaborator with industry and seen it go well and go poorly.

I've also seen lots of decisions made in drug development in terms of compromises in chemistry, shortcuts that are driven by just artificial deadlines. Like, look, this program's got to advance or we're going to kill it either in a young company with venture capital backing or in a big pharma company that says, look, we've got a huge pipeline. We've got teams competing against each other. We've got to win this pipeline down to best candidates. So we're going to make some decisions next quarter. So you show me what you've got in terms of chemistry advances towards your development candidate, and we're just going

to make a decision. I don't care if you think in another quarter you could do better. We're just drawing a line and making a deadline. That's the big company version. The venture investors draw different timelines in the small company context. I watch these things happen as an external collaborator for enough times and different compromises in what I thought bad decisions being made to say, I think there's an opportunity here to do what I say the best of academic medical work can be, here to do what I say the best of academic medical work can be, which is to lead by example, go into companies as a founder, meaning with an idea and try to do it the way that I think has the greatest integrity to the hypothesis that you're trying to test. Not everything's going to work.

That's not the point. It's just don't make decisions for the wrong reasons. Make them for the right reasons that the hypothesis is basically not held up and needs to be abandoned. You need to spend more time in optimization on the chemistry side. Your regulatory path needs to be innovative because it turns out that next generation sequencing is or isn't being adopted in the way that you thought it would be. I'm touching on some real examples here. Being in the boardroom, being around the table, the smallest table where these decisions are made,

I had no idea how satisfying that would be. Do I suggest it for everybody? Well, but I would suggest for everybody who cares about therapeutics related research, lab investigators, but particularly clinical investigators, is you need to understand to the best of your ability how people's worlds turn. You really need to develop that understanding. Otherwise, you cannot be an effective constituent. You can't be an advocate within your field for your current patients, for the future patients, next generation patients, patients worldwide who you're trying to advocate for. You can't do that if you don't understand what's constraining on the other side. That has been the lesson that I've learned. So the fact that I was approached and offered serially to

take light bulb moments and park them into companies, I couldn't have seen that coming eight years ago. Clinical investigators didn't have those opportunities. Should they have those opportunities? Well, you can imagine from what I've just said, absolutely. I mean, this is to me, I've got mentees in my own group and mentees elsewhere in the country who I look at and say, oh, this field needs more people like you around a board table. The thing that I've learned, and I hope that all of my co-board members, if they heard this, would understand how much I'm saying this with a lot of respect and even affection. These are super bright people who have accomplished in multiple dimensions. But if they are not an MD or MD-PhD or even straight PhD in biomedical research, let's say in cancer, there's a component that they don't see. able to provide that as a single person around a board of eight, that contribution can be

disproportionate. Not on the financing side, not on domains that I'm not very clever about, and certainly not very experienced about. Learn to appreciate those things. This is a seat that is currently not filled. I can only speak to cancer biomedical research in the private sector. This is a seat that's not filled. It's empty. There have been board seats held for basic investigators historically, but not the translational clinical investigator. And to me, I think this is, I'm not looking for more work. So this isn't at all about me, but I've seen that as cancer science has become so much more translational, the opportunity unfolded for me. And I think it would be a major benefit to the field for the private sector basically to engage more voices at the table of those who are involved in the truly applied science down to the patient

level. So you've got stakeholder representation in those discussions that includes the people who actually, in the case of cancer, hold the hand of a dying cancer patient, understand what the ramifications are of clinical trial decisions that are the most expedient path to approval versus the let's make this really stick and matter for patients. Doing this through scientific advisory boards, advisory boards, ad hoc consulting, which is the whole rest of my travels before I got into the entrepreneurial mode of actually launching companies. Been there, done that. Those meetings are held, they conclude, and life goes on. You don't have a fiduciary responsibility. That's exactly it. All of these companies, every single one of them, I mean, every company I've interacted with in biotech slash pharma, they will all say that they're trying to move the needle for patients, right? This is their stated goal, and I believe them. How do you do that if you don't have in the room, exactly as you say, invested, responsible leaders of the company, in the case of the board, who actually have career-long skin in that game. In retrospect, I don't get it, even though it wasn't there 10 years ago when I wouldn't have imagined that these doors would begin to open.

Well, that's a great way to close this discussion, Keith. I hadn't actually thought of it through the lens of the gap, the translational gap, per se. Well, I want to thank you very much. You've been incredibly gracious with your time and even more gracious with your insights. This is an episode where I learned a lot along the way, which always makes it fun for me as well. Thank you very much. Well, I appreciate the opportunity. Wouldn't be able to talk this long were it not for the fact that you're pulling out of me all the talking points that I've used in different venues at different times, but in one conversation. I think this is an incredibly exciting time in terms of understanding the molecular underpinnings of health and disease. Cancer is incredibly anxiety provoking. It's actually why I got

into the field, to be honest. It was the translating science to medicine and the most disproportionately havoc wreaking entity. And so I really appreciate opportunities, this being a really unique one, to try to help people understand this seemingly impossible-to-understand entity that is this kind of revolution within our bodies or betrayal within our bodies. But we'll get there.

The pace is quickening of progress. So I hope I've communicated that. But I hope you circle back to revisit this topic with others in the field because you will see year over year that the pace of progress will continue to advance. That'd be great. Or maybe I'll just come back to Boston once a year and I'll always time it in the nice time of year. All right. Thanks. You can find all of this information and more at peterottmd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode.

You can also find my blog at peterottmd.com. Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week email, where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, etc. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID PeterAttiaMD, but usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer, this podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. And note, no doctor-patient

relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and or advise, please visit peterottiamd.com forward slash about.