StarTalk Radio - The Biggest Challenge in Medicine with Dr. Linda Malkas

Episode Date: December 8, 2023

Why have we not found the cure for cancer yet? Neil deGrasse Tyson, Chuck Nice, and Gary O’Reilly explore paradigm shifts in cancer treatment, molecular biology, and a promising new cancer drug AOH1996 with City of Hope cancer researcher Dr. Linda Malkas. NOTE: StarTalk+ Patrons can listen to this entire episode commercial-free.Thanks to our Patrons Willie Bass, Nicholas A Jones, Edwin Goel, Joe Gibbs, Shane Alexander, Keith Goodman, and James Kuntz for supporting us this week.Photo Credit: Dr. Cecil Fox (Photographer), Public domain, via Wikimedia Commons Subscribe to SiriusXM Podcasts+ on Apple Podcasts to listen to new episodes ad-free and a whole week early.

Today on StarTalk Special Edition, we learn about a hopeful new direction of cancer treatments and how they work. Could we one day rid humanity of this terrible multifaceted disease? Up next on StarTalk. Welcome to StarTalk, your place in the universe where science and pop culture collide. StarTalk begins right now. This is StarTalk. Neil deGrasse Tyson, your personal astrophysicist, serving as your host. Today, it's special edition.

I got with me my special edition co-host, Gary O'Reilly. Gary. Hi, Neil. Yeah, former soccer pro and sports commentator. I also got Chuck. Nice, Chuck. Always good to have you, man. Hey, Neil. So today, we're taking up the top very serious topic, the emperor of all maladies, cancer. Oh my gosh. Gary, what did you put together for today? Well, finding a successful treatment for cancer has long been one of medical science's

biggest challenges, if not the biggest challenge. So, you know, with variable results and some rather nasty side effects. But there was one particular cancer researcher at City of Hope Cancer Research and Treatment Center in Los Angeles, decided, as she says, follow the science. And now we are looking at the possibility of a treatment that takes out the cancerous tumor, but leaves the healthy cells around it intact. I mean, this, yeah, wow. This is the kind of science that really could change people's lives. And by the way, our guest once dreamed of being an astronaut.

So, Neil, yes, if you would like to introduce our guest, I think we're going to have an interesting show. Okay, I'll introduce anyone who ever dreamed of becoming an astronaut. Linda Malkus, PhD. Linda, welcome to StarTalk. Thank you so much. It's an honor to be here. You're Associate Chair and Professor

in the Department of Molecular and Cellular Biology at the City of Hope Cancer Research and Treatment Center. So I'm just glad places like that exist in this world. And you have clinical expertise in molecular diagnostics and experimental therapeutics. So it sounds like you're all up in this. And so just welcome. And tell us about cancer. Like what?

I have basic understanding of cancer. What, Chuck? What do you ask? I was going to say that sounds like the worst bedtime story request ever. Read to me about cancer. Tell me about cancer. Tell me about cancer. So cancer is hard to treat, as I understand it, because the cells look just like your cells. So anything that would kill a cancer cell is going to kill your cell.

And that's the beginning and end of what I know about cancer, basically. So what can you add to that? And what can you tell us about the new treatment? Well, actually, you got a really good start with this in that cancer, I guess, in my opinion, is really kind of a way the body turning on itself. And cancer is like, you know, being that I am, you already know, I'm, you know, like a science fiction geek. So alien, you know, if you think of the movie Aliens, you know, you can think of cancer as, you know, the most perfect predator, you know, it really is. And it's why it's so hard to treat because it looks like us. It's our own body. It knows all our own

tricks, you know, how, you know, it's our processes, which it uses against us. And then cancer also has this ability to constantly evolve. It's actually a very scary predator. It really is. And that's why it's so very, very hard to treat because it's constantly changing itself. It is such a weird entity. That's how I, you know, and I used to, when I was first studying, you know, I would really look at it as like a, you know, it's a cell, you know, but it's almost like a living entity. It is, you know, because it can evolve. It has, you know, normal cells. They have these, you know, if you think about it, every day. And I want to congratulate you all.

You're all cancer survivors. Every one of us, including myself. Every day since before we were born, we make at least eight cancer cells. And our immune systems take them out. So we're constantly making. So we have eight cells per day. Per day. Every day. Per day. Okay.

Per day. Every day. Okay. So we're making at least eight cancer cells every day. And your immune system is constantly surveilling and taking them out. We also have these other wonderful processes in our cells. We are constantly making DNA damage. Just the act of eating and metabolizing food, you're actually making free radicals, which are attacking your DNA. We have these wonderful DNA repair systems

that go in and just clean it all up and the cells divide. We're rather a miracle that we're here and there are not giant tumors as it is. A cancer cell... It's true. It's true.

It's a miracle that we are ourselves and not just tumors walking around in civilization. Tumors with eyes, you know? That's a sci-fi story. I'm glad you're hearing myself. So, you know, you have these cancer, so you have cells, these, you know, they become cancer cells. You know, they're started by DNA damage, okay, or a mutation. I mean, that's the heart of what cancer

is, a change to your genome, change to your DNA. But what happens with cancer cells is they go on to make DNA, their DNA damaged themselves. it's called constitutive replication stress. They are continually damaging themselves. And you think about that, you go, why would a cell continue to make damage? It doesn't make sense. It's like, why are you continually mutating your own genome? retaining your own genome. But that is, the way I look at it and others is actually, it's an almost an evolutionary mechanism for them. Like I said, you know, every day we're making cancer cells. We have this incredible immune system that's constantly surveilling and, you know, taking them out. So for a cancer cell to survive, it needs to constantly change itself

so that it can avoid the surveillance system. It sounds eerily like a virus, the way that you explain it. It's diabolical. Yeah, yeah. And, you know, it's interesting that you mentioned the viruses because, you know, it's very interesting because, you know, there is, that you mentioned the viruses because, you know, it's very interesting because, you know, there is been thinking for a long time, you know, that ways to even treat some forms or cancer could, you know, could we use things that, you know, we use to target viruses?

We use them for cancer. So it's a scary thing. I don't want to scare your audience, but... You already have. Let's get away from that. Spoiler. So good things. So, you know, practice good health.

No, I can't get walking tumors with eyes out of my head. Yeah. Because of that. So what is this treatment that has 1996 in the title? What is this? So if you look inside the human cell, there's a nucleus, right? You know, I always call the nucleus like the house of DNA. Okay.

So in the house of DNA, you know, the human cell harbors three feet of DNA inside the nucleus of every cell. If you uncoiled it. Uncoiled it all out and stretched it out linearly. Three feet of DNA is shoved into something we can't even see. All right. Do you know if you took all the DNA of every cell

and tied it end to end, that the person will die? Well, probably. But also, if you took all the DNA out of one human and stretched it out into his face, it goes beyond the sun. Wow. Just from one human and stretched it out of his face. It goes beyond the sun. Wow. Just from one human? Yeah, that's how much genetic information we harbor.

That's how much genetic information we harbor. We are amazing machines. And the person dies in that case too. Especially if you get close to the sun. So our gut, we're like a tube within a tube. So your gut turns over like every two to three days.

So there's a lot of cell division that goes on in your gut. And every time your gut cells have, or any cell in the human body has to divide, what you do is the mother cell has to make a whole new complement. So that's another three feet of DNA stuffed inside of one nucleus. And then it's those two cells in the DNA are divided out. So I got really interested how does a human cell replicate its DNA in such a confined space and inside of like eight hours, it makes that. There isn't a human machine that we have invented that can actually do anything near this with such incredible fidelity. So I got involved in studying DNA replication complexes. And so that was my first

foray into molecular biology is actually understanding the DNA replication process. And then, you know, as an independent investigator, I started reading about cancer. And cancer, you know, is a disease of DNA damage. That's really what cancer is. The crime scene of replication? Yeah. And here, like Agatha Christie, here she goes. So I go and I said, you know, I'm like the mother of replication complexes. I literally can isolate from a human cell a replication

complex, put it into a test tube, offer it DNA, and it would make DNA just like inside the cell. So I said, gee, I wonder if this complex is different in cancer cells versus normal cells. And I won't go into the gory details, but the bottom line was, yes, it was different in cancer cells. Cancer cells corrupt the DNA replication apparatus so that it allows a sprinkling of DNA damage every time it makes it. So actually, you can almost think of the daughter cells of a mother. Cancer cells are different from its own mother. That's how it changes.

So since I knew a lot of the proteins that were inside of this replication machine, I started looking through who was different. And we found one protein, which I didn't think would it be the protein. I thought it was going to be one of the cool DNA polymerases, but it wasn't. It was a protein called proliferating cell nuclear antigen or PCNA. Now, way back when, when we first found this altered form of PCNA, people would never have looked at it. They always think it was like this. So it's called a sliding clamp protein. And I liken it, okay, like if you think of DNA as like a shower curtain

ring, PCNA is kind of like a shower curtain ring. So PCNA is a sliding clamp protein in the circle's DNA. And what it does, it tethers three other molecules that have to work at DNA and allows them to process and do whatever it is that they have to do. Now, the cool thing about PCNA, now you're getting me. I hope I'm not boring you guys because this is like, this is it. Okay, this is it.

Go for it. Bring it on. Okay, PCNA, okay, interacts with at least 200 other proteins in the human cell. It has by protein-protein interaction. So we found that PCNA was different in cancer cells compared to normal cells, and that that difference in PCNA correlated now with this

funky replication act, right? I mean, you know, technically, we found a new molecular target, this PCNA that's different in cancer cells. And it's not changed in the genome. It's not changed because of RNA. If I was to develop a drug to that PCNA, to the form that's only in the cancer cell and not in the normal cell, several things come from this. One, I would target and knock out only the cancer cell because that drug would only be effective inside the cancer cell to kill the cancer cell. But it would also be super effective because it's not just attacking one protein, it's taking out an entire network of 200 protein functions inside of the cancer cell while leaving that same network in place in a normal cell.

That is the heart of what AOH-1996 is. So this was a race to find something different about the cancer cell that had eluded people. It totally is. It has so many novel features to it. I'll be very honest. When we first found it, you know, everybody wonders, how come it takes so long to do cancer research?

Why can't they do these things fast? Is that what we sound like to you? No, that's a great question. I'm on a lot of airplanes, and I'll sit next to people on airplanes. This has to happen to you too, but I'll sit on airplanes and I'll tell people when I, you know, I am a cancer researcher. I get a couple of different things. One is, you know, they already have the cure for cancer.

They're just holding it back. You know? Oh God. You know, they make so much money off of treating cancer. They can't cure it. And I'm just like, can you imagine how much money they would make off of a cure? That's what I always say. So then the other thing I get is, you know, why does it take so long? Because, you know, finding a target, moving it forward, you know, this target was so different.

I actually went to a very large pharma company way back when. So this is when I first found it. And I said, hey, I found this great molecular target. Can you help me make a drug to it? And they said it was undruggable, that there was no way. Why was PCNA undruggable then? What was it about that particular protein that made it? It's changing.

There's dogma. Okay. There's some dogma in the field. And dogma was you only make a drug against an enzyme. And so it was quite crushing to me when I went to this very large pharma company and I danced for them. You know, I took all eyes. I took all, I talked about reputation conflicts. I was dancing for them and saying, this is a great target. And they're very

kind. They were listening to me and they said, undruggable. You'll never be able to make a drug to this. It's involved in protein-protein interactions. It's an indigestible protein region. It's impossible. And I just, you know, when I left that place, you know, I said, oh, my God, how could I have been such a, how could I have been so, you know. But by the time I made the parking lot of that place, I was like, I'll be damned. I'm going to try to figure this out. Wait, don't tell me you found a solution just to spite somebody. No, no. Actually, I did it.

No, no. Whatever the motivation is, I guess. No, no. I made a promise to a family that I was going to go and try to do something about cancer. Oh, wow. So there's an underlying heart issue here. Okay.

There's a noble cause. There is a very noble cause. Yes. Spite sells better though. Let me just tell you something. When we make the movie, when we make the Linda Malkus movie about the treatment

and the cure of these certain types of cancers, the spite angle is what we're going to go with. You know, spite is great. You know, spite is great fuel. Yeah. But it won't hold you for long term. That's a very good point. Agreed.

That really is a really good point. You know, you can only go so far because, you know, you just run out of fuel. But when it's a heart issue and it's a promise, that's something else. So, okay, I'm going to dub you the queen of different thinking just for the moment. Was there other different thinking that had to follow your initial thought process that obviously was different to everyone else's that led you to IOH 1996 and its efficacy? Well, so there is this, so you think about how this drug is working. It is very different.

Okay. It wasn't an enzyme targeting an enzyme. And my thinking was, yeah, I speak a lot in analogy just because it is new concept. So I always, one of the things I, one of my academic positions, I was in Indiana, the Indiana University School of Medicine. And I found that one of the ways that you shut down most of the air traffic in the United States, And I found that one of the ways that you shut down most of the air traffic in the United States is you send a snowstorm into O'Hare. And you shut down all those routes. So PCNA is a terminal.

Okay, it's a hub. It's an okay. And you're shutting down 200 flights out. So literally what I'm trying to do is build a snowstorm. That's brilliant. what I'm trying to do is build a snowstorm. That's brilliant. Because going back, that's going back to this sliding clamp that you talk about, these proteins all being connected. And so what you're doing is you're coming in and you're saying, I'm not going to treat this. What I'm going to do is shut down the system inside of the system. Shut down the whole network. shut down the whole network, shut down the whole thing.

So that was really different. And as luck would have it, this place called City of Hope called me out of the blue and asked me if I would be an external advisor for them to come in and review their research program. And so when I went there, I was blown away because they had put together this incredible apparatus, which I hadn't seen inside of an academic institution before, where they had put together all the people, the resources, and the facilities for actually taking an idea off a lab bench and moving it to the clinic. And it was like, this is where I got to go. So now PCNA. So I moved to City of Hope and they're wonderful. I've got with all these

great minds, right? But I still had to do a lot of molecular biology, even to get them to be able to work on what I needed to do. And what I had to do was figure out where on the PCNA molecule was the business part for the cancer. And so what I did was I got the PCNA gene out, and we made mutations through PCNA. And we made antibodies, all kinds of things. And we were actually able to define a small domain of about 10 amino acids, which was the difference between cancer and normal. Once I had that address on the protein, so, you know, every protein is so beautiful. Each one has its own crystal structure. You know, if you look at the crystal structure, every protein is like beautiful. Each one has its own crystal structure. If you look at the crystal structure,

every protein is like its own fingerprint. So I found on this big protein this little bitty address. But that address had formed a pocket inside of the molecule. And once I had that pocket, that's when I could start screening for molecules. And we screened through 6.5 million molecules that would sit inside.

And this is humans or is it some form of AI doing this? It's a form of AI. So it's you use these gigantic, so this is so cool. I mean, this is called virtual screening. So they have these fantastic computers

with these databases of molecules. And they're like from everything, from trees and mushrooms and from everything, any kind of structure. So the 6.5 million molecules, and you take your protein, that 3D form of your protein, and I got that little packet sitting inside that protein. And you take that structure and that little pocket and you stick it in the computer and the computer goes 6.5 million times this way.

Right. To see what puzzles together. Right. And it came up with 53. 53 out of 6.5 million. And we took them home and we tested 53 compounds on normal versus cancer cells. And of the 53 compounds, we found five that killed the cancer cells and left the normal cells alone. And left the other cells alone.

And it was like, oh my God. But that doesn't mean anything. It's on a lab bench. How do I bring that forward now from a lab bench? And the work has been duplicated? Yeah. I mean, this is, you know, actually, you know, we've moved. So then it becomes this incredible process of, you know, having that, what they call it, a hit.

So of those five molecules, we picked one. Very unique structure. Nothing looked like it chemically. And we moved it slowly forward through the process. And it became AOH-1996. It's in clinical trial now. It's in a phase one trial. With humans?

Is phase one with humans? In humans. What phase is with other animals? Okay, so. Is that one of the phases? So the workup to get to the FDA, you have to do testing in animals. We did it in mice and dogs. in animals. We did it in mice and dogs. And the beautiful part of it, of all that testing was,

it did not show toxicity. We never found the maximum tolerated dose. The animals are very happy on it. I mean, they eat, they show no neurological problems. And in tumor models, animal tumor models, we show that we could inhibit tumor growth. And with all that data, you go to the FDA, and then they granted permission now in the phase one trial. And the phase one trial, so there's three levels of trialing to move something to that, you know, it can be used in the clinic. Phase one is a toxicity trial. You know, can we find the maximum tolerated dose in humans? I have a strong suspicion we won't. And then you go on to now efficacy trials. Those are called phase two trials, where, you know, do you see any effect on a person with tumor? And then phase three are these large trials, you know, over different populations and things like that.

over different populations and things like that. You describe cancer as a molecular signature disease. I can say that, but I'm not quite sure I'm anywhere near qualified to explain what that means. So would you, in terms that I might understand what that actually means? Because you don't see it as singular. You see it as multiple diseases, don't you? Yeah. So, you know, when I was learning, you know, I was training, cancer was really thought as like one thing. You know, you had breast cancer.

You had lung cancer. You had prostate cancer. You had, you know, whatever cancer. It was one type, right? And I used to work with a wonderful breast cancer oncologist out in Indiana. And he said it used to drive him crazy. He said, Linda, I'd have two women who come in with breast cancer in my practice. And everything about them is the same.

You know, they grew up on the same street. They have the same number of children. Everything I could measure about them was the same. He said, I would put them on protocol, and one would respond beautifully, and one would die. And there was no way to tell the difference. That was our thinking for so long, that cancer was one thing and a cancer type was one thing. That has totally been radically changed because cancer is probably as individual as your fingerprint. Wow. Cancer as it affects the individual.

Yes. Your tumor. Yeah. That makes sense. So you think about your tumor now. Your tumor has its molecular signature. You know, the thing that's, that, you know,

there's a lot of unique features. That's why, you know, this molecular signature part of cancer is such a huge breakthrough. They call it precision medicine now or moving towards precision medicine. Is that the same thing as designer medicine? You're getting there. Seriously, you're getting there. Okay.

Seriously, you're getting there. So, you know, and if you can think, the other thing that we had, very myopic vision, was that tumor was all by itself. But you also have to recognize that the tumor is sitting inside of a host. So, the environment around a tumor is going to influence cancer activity just as much as the tumor itself. If I'm not serving dinner at home, I don't like being called a host. There's something about that. I'm cool with it as long as there's not a parasite involved.

I'm all right with it. That's what I'm saying. That's my whole point. I'll tell you, cancer is a parasite. It just hasn't figured out how not to kill hosts. It is a I'll tell you, cancer is a parasite. It just hasn't figured out how not to kill hosts. It is a parasite. I mean, cancer is a parasite. So now a person comes in to the clinic. You have their genome read.

And you can actually figure out, we're moving to this. We already do it in some cancers. But you look at their molecular signature and you're starting to say, oh, well, you know, this drug works better in this place. And even if the drug was found in lung cancer, but a woman could come into the clinic with breast cancer with the molecular signature of a tumor that would really work well with a lung drug. I mean, it's really amazing. We're really in a very, very different kind of time and a revolution in time and thinking. So what is the evidence that one kind of cancer

migrated from one organ to another? Okay, well, that's... Because many women with breast cancer die of breast cancer, right? Evidence that one kind of cancer migrated from one organ to another. Okay. Well, that's. Because many women with breast cancer die of brain cancer. I don't want you to get confused. I don't want you to get confused. Yeah. I don't want to.

Yeah. So there's actually two things going on. One is metastasis. Metastasis. You know, where, you know, like a woman has a breast cancer and they will likely metastasize to bone or brain. I mean, it's kind of like it has a homing device. It will go there.

It likes that environment, you know. The other thing that I want to stress is the molecular signature is not about metastasis. Sometimes the things that are helpful to a tumor to grow, whether it's breast or lung, are the switching on or off of particular genes. So that is the molecular signature that could help us potentially

either use current therapies or make new therapies for. That's a base molecular signature. Metastasis is a whole nother animal. So can I ask you about when we first started? So you said that we produce eight cancer cells per day. How does this treatment differ in our body's eradication of those eight cells? And why don't we just try to replicate what the body, so you have this antigen, is our body making an antibody that actually just kills these eight cells?

Exactly how is the body killing the eight cells and why aren't we trying to replicate that? So it's good that you bring these things up. So that, you know, one of the big arms or areas of research that is going on is immunotherapy, right? It's like harnessing the power of the immune system. And so you have, you know, they call them CAR T-cell therapy. There are immune checkpoint therapies.

Huge. This is an amazing question. I mean, obviously in a fully functional person, our immune system is keeping things in, they're keeping cancer in balance. You're in check. They're keeping it in check. Whatever reason we become out of balance

or you're exposed to some environmental cause you can't the body doesn't maintain that balance anymore so there are wonderful arms of research summits going on at City of Hope

very very exciting where they are exploiting now or trying to understand how to better harness the immune system. We know a lot about it, but we're still in the very early stage. And it's such a powerful weapon. But you know, the thing is, but I have to go back. Cancer constantly is figuring its way around things that we throw at it.

Way back when, when I was training, everybody said, we're going to find the cancer gene, the cancer gene. Turns out there's lots of cancer genes. And then there was something called tumor suppressors on top of it. I do not believe we will ever have a single therapy. What we will have is, and I believe AOH-1996 is going to serve as one of the agents in an arsenal. We already have an arsenal, but the object is with using precision medicine that we are able to turn cancer from a critical disease into now a managed disease. And we're moving towards that.

I actually have a friend who had breast cancer, and she never went into remission. She lived for 12 years. That's kind of like prostate cancer. Totally. Most men die with prostate cancer because it's such a slow-growing cancer that sometimes it's like, well, we keep an eye on it. There's no need to do anything invasive because you'll be dead before it kills you. Yeah, but it's a very painful cancer for men. It really is. Oh, I did not know that.

No, actually, if it progresses for them. AOH-1996 is administered as a pill. Yes, twice a day. Why a pill? Why isn't it injectable or some other form of approach? Okay, so why a pill? I wanted to make it easier on the patient, as opposed to them having to be hooked up to infusion.

But also, based on the chemistry of the drug, it has a half-life of about five hours. drug, it has a half-life of about five hours. And so in order to keep the drug present all the time, it needs to be administered twice a day. So a patient isn't going to come in and be hooked up to an infusion all the time. So it's, so it's a continued, you know, the patient comes in, uh, they are, you know, our phase one patients come in, they are, you know, checked for, you know, certain how they're doing and everything. And then, uh, they're given their pills and they, they go home and they, they take it. And so they take it twice a day. So Linda, I heard you use the term half-life. Is that in the way we would use that term in physics?

Yeah. Where after a certain amount of time, is half of the thing that matters that's still active? Yes, absolutely. Absolutely. So the body, you know, the drug is metabolized, you know, eventually. A metabolist, that's what makes it up. Yeah, it has aized, you know, eventually. Oh, metabolized. That's what makes it up. Yeah, yeah.

So it has a half-life metabolism. Yeah. So after five hours, there's half of the drug. And after another five hours, half of what that was. Right. Half of the half. And so then you got to pick it back up with another dose. Right, right.

So I get it. Okay. Yeah, that's like, you know, like anybody taking antibiotics, you know, some people have to take it three times a day or twice a day. It has to do with maintaining a drug level. I understand it precisely with that terminology, but I've never seen the term half-life on a bottle of drugs. They should put it on there. Those are the things behind the label.

Yeah, they should put it on there. Those are the things behind the label. Yeah, they should put it on there because it's so important. Like when you said antibiotics, a lot of people screw up their antibiotics because they're not taking them when they're supposed to take them or they don't finish them. And it's so important that you do that

because of that reason. So maybe they should. It might make it a little more urgent to them. It might make it more urgent if you said like. Any drugs, you know, if they say, you know, take it every eight hours, it all has to do with the drug half-life. Right. Yeah.

That's a good thing to know. I will henceforth think of it in those terms. Yeah. It's the half-life of my aspirin. Right. Right. Yeah. I'll tell you the half-life of aspirin, children.

I'll tell you the half-life of aspirin, children. You said AOH-1996 would most likely be most effective as a combination therapy. Is that going to be beneficial for cancer resistance as opposed to like a single pathway therapy? It's actually a wonderful question, Gary. Thank you. So one of the problems with cancer, it's a pain in the butt. Remember, it's this evolutionary thing going on with cancer. So a woman has ovarian cancer or a person has lung cancer

and they are treated usually with a platen compound write-off. What's a platen compound? They're chemotherapeutics that attacks DNA. So it's also very toxic because it can't tell the difference between a normal and malignant cell. So it's targeting proliferating cells, which are cancer cells, but you also have a lot of proliferating cells that are healthy. And that's why so many chemotherapeutics are horrible because they're targeting proliferating cells and they can't differentiate it between normal and malignant. And so, platen compounds are ones that target.

Right, just so, for example, as we came to understand it, your hair grows faster than most other things in your body. So, that would be a byproduct of the targeting of proliferating cells. Yeah, so your eyebrows, your toenails come off. These are horrible. These side effects are horrible. You know,

you lose, I mean, it's, you lose your eyelashes, you know, your tongue, you know, your gut.

Remember I told you your gut is turning over two or two, three days rapidly. That's why so many chemotherapeutics really have such bad GI effects. But going back to Gary's question about combination therapies and resistance, well, one with AOH-1996, if it holds up for being very non-toxic and effective for treating cancer, of course, you can now, what you do is you, and not just AOH-1996, this happens all the time. The thinking now is we're not going, it makes big pharma unhappy because they always want one big drug, you know, that's going to treat everybody. But now that the one big drug, or they call it monotherapy, we're moving away from monotherapy and more going towards what they call cocktails, okay,

is that you will put together a variety of drugs, you know, like treating testis cancer. Chuck knows a lot about cocktails. I knew that gag was coming. So my joke is that AOH-1996 will be the olive in everyone's cocktail. So, like that? So, two things with AOH-1996, great hope down the line if it proves to maintain its non-toxicity. I hope that we've already done studies in animals to show that it complements a variety of currently used drugs.

variety of currently used drugs. And in the presence of our drug, we can actually lower the amount of some of these very toxic drugs very significantly. So the animals can have, you know, they can still show very effective growth inhibition of the tumor, but they're not sick. You know, they're not as, you know, so that's one thing. But your thing about resistance, this has come up a lot for me for this drug, for AOH-1996. My lab has worked really hard at trying to make resistant cancer cells to AOH-1996. You know, cancer cells love to do this. I mean, like I was talking about the patient, the lung cancer, ovarian cancer patient, they respond beautifully, but in a year or two, their cancer comes back and they're resistant now to like cisplatin or carboplatin. AOH 1996, we can't make a resistant cell so far. And I'm thinking why.

Like a lot of the therapies that are made against kinases, single enzymes, remember they do one function. And what the cancer cells do, because it's such a little, you know, it goes, you know, so you're treating, you know, like with a kinase inhibitor. Cancer cells will now change the enzyme that that used to target, that that drug would target. So now it's resistant to the drug. And cancer figures a lot of different ways to become resistant to drugs.

This is amazing. Cancer is an amazing... It's unbelievable. Is there such a thing as cell intelligence? I'm trying to figure out, because as I hear you talk about this and I'm thinking about viruses and these cells that tend to adapt and change and, you know, reconfigure,

it's like, what is going on that this can happen? Is that just part of our evolutionary process? What is going on? It wants to survive. I would take a stab at that. There's billions of them. Yes, exactly. Billions and billions.

Yes. So, most will die because they can't adapt to the thing. The few that do, bada bing. There you go. That makes perfect sense. Bada bing. Look at that. Awesome.

Now, if you think about it. So, Linda, I just spoke up out of turn. No, you did great. No, you did great. Give me a break. There you go. You did good. So, Chuck, when it's a game of numbers,

there's always somebody who's going to slip through the gate. Somebody's going to slip. Yep. Look at that. And remember, and it's constantly changing its genome. It's like locks, you know, it's changing the locks. Right. So with resistance now, what I'm thinking with our drug,

it's not a single enzyme. It's a herb. You'd have to change all those gates all those proteins coming in and going out so I have the hubba hubba hypothesis

for treating cancer hubba hubba so by attacking a hub like PCNA because it controls all this network, if we could identify other networks like PCNA and start targeting hubba hubba, you really would find them very cancer-specific. But as opposed to the very long-time strategy of just targeting a single enzyme, you should, you know, for you guys, okay, as opposed to start targeting a single star, you do a whole galaxy, you know? You target galaxies. Hubba hubba. Amazing.

So, Linda, just, so take us out here. What, in five years, 10 years, what does the world look like? In five, 10 years, because it's just been amazing what the last 10 years, I mean, things have changed so much in the cancer therapy field just in 10 years. You know, from my training in the last millennium, okay, last century, you know, where we thought, oh, we're going to find one cancer gene, one drug, one drug's going to do it all. You know, we were so naive to now the basic understanding that everyone's tumor is different. But now with using molecular signatures, we're getting every tumor's address.

We're figuring out where they live, okay? Not just locally, but figuring out- I know where you live. There you go. I know where you live, Tana. I know where you live. That's exactly what we're being able to do. Chuck is getting Philadelphia on you right there.

Backwoods Philadelphia. Well, you don't have to come see me. I'll come see you. Exactly. Okay. Exactly. But, you know, the thing is, is with figuring out the underlying molecular signature

of each tumor, person's tumors, their personalized signature of that tumor, and now coupling it with this molecular signature, you respond to these subset of therapies. So when a lady comes in with breast cancer, subset of therapies. So when a lady comes in with breast cancer, you can say, Mrs. Doe, you have breast cancer 6A. And we know that 6A responds to this cohort of drugs and will effectively treat her. And she may be cured. And if she comes out of remission, we check that signature again. And we say, wow, we use this cohort of drugs. So I see great things. It's like walking into a store, buying a suit off the peg,

or going to Savile Row where the best tailors in the world are. I love it. Exactly. Just for you. There you go. That's fantastic. Bespoke drugs. All right. Linda, you said you're from Queens, New York? Yeah, that's in Heights Flushing. Yes, yes.

Cancer never stood a chance. She's from Queens, New York. What high school did you go to? So, yeah. So, high school, I went to St. Agnes in College Point, Queens. St. Agnes. Okay.

Yes. And then for school, I'm a graduate of City University of New York, Queens College. See, it's CUNY. That's where it happens. A Chuck Lou person.

Yeah. Yeah. Charles Lou teaches there. Yeah, we got it. All right. Well, Linda, thank you for being on the show. Oh, thank you. Thank you for having me. Yeah, we got it. All right. Well, Linda, thank you for being on the show. Oh, thank you.

Thank you for having me. Thanks for sharing your expertise. And keep at it. Thank you. Stop talking to us. Get back to the lab. Absolutely. Absolutely.

They're in there. Okay, they're in there working. Trust me. Good. All right. All right. All right, Gary. Good to have you, Gary.

Pleasure. So glad we had a chance to tell this story. Yes. All right, Chuck. Good to have you, Gary. Pleasure. So glad we had a chance to tell this story. Yes. All right, Chuck. Good to have you there. Always a pleasure. Neil deGrasse Tyson for another edition of StarTalk Special Edition. As always, as Linda taught us once again, keep working out.