The Peter Attia Drive - Qualy #61 - Rapamycin in cancer treatment

Episode Date: November 19, 2019

Today's episode of The Qualys is from podcast #10 – Matt Kaeberlein, Ph.D.: rapamycin and dogs — man’s best friends? — living longer, healthier lives and turning back the clock on aging and age-related diseases.   The Qualys is a subscriber-exclusive podcast, released Tuesday through Friday, and published exclusively on our private, subscriber-only podcast feed. Qualys is short-hand for “qualifying round,” which are typically the fastest laps driven in a race car—done before the race to determine starting position on the grid for race day. The Qualys are short (i.e., “fast”), typically less than ten minutes, and highlight the best questions, topics, and tactics discussed on The Drive. Occasionally, we will also release an episode on the main podcast feed for non-subscribers, which is what you are listening to now. Learn more: https://peterattiamd.com/podcast/qualys/   Subscribe to receive access to all episodes of The Qualys (and other exclusive subscriber-only content): https://peterattiamd.com/subscribe/  Connect with Peter on Facebook.com/PeterAttiaMD | Twitter.com/PeterAttiaMD | Instagram.com/PeterAttiaMD

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So without further delay, I hope you enjoy today's quality. And so there's really two different questions. The first would be, if you take a patient with cancer and you inhibit M-Tore, is it not helpful because the tumor has already evolved so much to be outside of M-tours per view, or is it, it's actually harmful, and that's of course separate from the option that could be helpful. Right, so my understanding of the clinical and the literature in humans is that for most cancers, once it's reached the point of diagnosis that rapamycin is disappointing in its effectiveness.

It's not particularly effective. That's not true for all cancers, but for most cancers, it has not been as effective as you might expect, given that we know that activation of mTOR is common when you get high proliferation, and that turning down mTOR should stop that. Turn off the proliferative cell. So I think you're probably right that at least part of the story is that one of the steps in the progression to cancer is evolving to ignore the break of turning down MTOR. So rapamycin may not be effective there. I think it's a complicated system though because the effects of rapamycin on the immune system

could have beneficial effects in terms of cancer or detrimental effects. So we know that immune surveillance is probably the most important anti-cancer mechanism. We're certainly one of the most important anti-cancer mechanisms. And we know that immune function goes down with age. That's probably one of the reasons why most cancers are age-related. So if you can boost age-related immune function with rapamycin, enhance immune surveillance,

that's gonna have a potent anti-cancer mechanism. And again, this is my guess. My guess is that's why we see in the studies in mice that cancers are pushed back during aging by rapamycin. On the other hand, if the dose of rapamycin is high enough that you're actually inhibiting immune function, that could be... That could amplify. It could amplify.

There's not a lot of data yet. So we did one study in my lab where we gave mice, I think it's the highest dose that's ever been given in the context of an aging study. This was a daily injection of 8 milligrams per kilogram. So as we call it the party dose. Yeah, right. Right. And so this was a study where we only gave the mice,

Rapa Mison, for three months. So this was from 20 to 23 months, and then we stopped the treatment. And what was interesting there was we got completely different effects in male mice versus female mice. The male mice lived 60% longer after the end of treatment. They had better muscle function. They got less cancer. The female mice had no difference in lifespan. The mice that got

rapamysin or didn't get rapamysin. But they died with, I want to say from, but it's hard to say for sure what a mouse dies from. They died with very different types of cancers. So the female mice that had gotten this high dose of rapamice in for three months all had aggressive hematopoietic cancers. Whereas about, I think it was about 30 or 40% of the vehicle treated mice. So in black six, that's not an uncommon cancer to get. But none of the rapamice and treated mice

had non-homatopoietic cancers. Whereas like 60% of the mice that didn't get rapamycin. Now the 2009 study that kicked all this off actually showed a greater survival benefit in the female mice, didn't it? That's right. So I think, and again, this is a guess, because I don't actually have the data to back it up.

My guess is that because we pushed the dose so high, we might have actually taken it too far in the female. So one school of thought is that female mice at least, we don't know if this is true in any other organism. Female mice are more sensitive to rapamycin. And that could either be that they don't clear the drug as quickly or that for whatever reason in female mice, the same amount of rapamycin has a greater emtory inhibitory effect. But that's one school of that.

And I kind of think that's right. So at lower doses of the drug, you see a bigger lifespan benefit in females than in males. Did you repeat that experiment at like four makes per gig or something different? We haven't. We haven't. We should. So we did do... We just need to...

I'll tell you... I'll tell you... ...a infinite pool of money to do all of these, like just... ...anastralist questions. That's a figure out of the most important questions. Yeah, just answer all the questions. The most important questions. Yeah, and I think the dose response is really important. We did do a lower dose for three months as well. And there we saw increases in lifespan in both males and females,

roughly the same magnitude. So it was that dose was nine times higher than what the ITP tested. Wow. So one of the things that's interesting though is as you go higher in dose, so three times higher than what they originally tested, the females still live a little bit longer, but the difference between males and females, the gap has closed quite a bit. So I think that females, for whatever reason, at a given concentration of rapamysin are just

more affected by that amount of the drug. And I think what we did in our high dose study is we just pushed it a little too far. We pushed it to the point where rapamycin did something, probably to the immune system, that allowed these immune cancers to escape surveillance or become hyperproliferative. And again, I'm not a cancer biologist, I'm not an immunologist, so I don't have a good feel for what the mechanism is. I can tell you what the observation is, and that's that all of those animals had aggressive, hematopotic cancers when they got this three months of rabbi, Mison.

Just out of curiosity, more B cell or T cell, do you recall? I don't recall. It's in the paper. We could look it up. Because there's an opportunity here to do the reverse, right? I mean, there's an opportunity to take, right now we're seeing just an unbelievable amount of activity in adoptive cell therapy.py. Or even when you just talk about

like checkpoint inhibitors and things like that, like it makes you wonder, are there ways to make these things better? Maybe the checkpoints are a wrong example because you might get more auto-immunity. But certainly when you talk about adoptive self-aeroppy, anything that could boost either, you know, CD8 function or inhibit the regs or something. There might be ways, like I almost make you wonder if using rap amycin in a different manner in combination with immune-based therapies might make more sense. Yeah, I know, I think there's a lot that could be done there for sure. Part of the reason why we haven't explored this in more detail, well one reason is again,

as I said, I'm not a cancer biologist, so it's not the thing I'm most interested in. I think it's really interesting biology, but it's not the thing I'm most interested in. But I also feel like, because the dose that we gave was so high, that, again, thinking translationally about rapamycin as a drug in the context of aging, my feeling is that what we've uncovered here is not going to be relevant at the doses that we would think about giving to you the dog. Yeah, yeah, yeah. So that's why I haven't really spent a lot of my time trying to figure out what's going on there.

But I think, certainly in the context of cancer immune therapies, I think we do need to think a little bit more about how effective those kinds of therapies are going to be in the elderly and maybe something like rapamysin could help, could actually enhance the ability of those therapists. I mean this question you posed when David, Sabatini, Tim Ferris, and Napcentle and I were in East Ireland a year ago, over a year ago, this might have been our favorite meal time discussion, which is what best explains the increase in cancer incidents with age, being in other words, when the primary driver be the reduction in immune surveillance

or the length of time to accumulate mutations or the frequency of mutations, I mean, it's not an obvious answer. And I don't think it has to be just one. No, exactly. I think all those things has to be just one. No, exactly. Almost all of those things. So it would be all of them together. Yeah. Yeah. I certainly, over the last few years, have come to think that the decline in immune function is, it's certainly more important than I had initially thought.

That's my advice. I mean, I secretly want that to be the biggest driver because I think we have a better chance to control that than some of the other ones. And I think it probably is. That would be my guess. And I also think it kind of makes sense that if you have an immune system that's functioning the way it's supposed to,

you can actually deal with the mutation accumulation because your immune system has been a clear of those before they become a problem. I hope you enjoyed today's quality. Now sit tight for that legal disclaimer. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional health care services,

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