Qualy #61 - Rapamycin in cancer treatment


Procam to the quality's a subscriber exclusive podcast qualities. Just shorthand slang playing for a qualification round. which is something you do? Prior to the race just a little bit quicker qualities podcast features episodes that are short. And we're hoping for less than ten minutes. Each which highlight the best questions topics tactics etcetera disgust on previous episodes of the drive. We recognize many of you as new listeners. To The podcast may not have have a time to go back and listen to every episode. Those of you have already listened may have forgotten so the new episodes of the qualities are going to be released Tuesday through Friday and they're going to be published exclusively in our private subscriber. Only podcast feed now occasionally. We're going to release quality episodes in the main fee. which is what you're about to hear now if you enjoy these episodes and if you're are interested in hearing more as well as receiving all the other subscriber exclusive content which is growing by the month you can visit us at PTA DOT com forward slash? Subscribe it's without further delay. I hope you enjoy today's quality and so there's really two different questions I would be if you take a patient with cancer and you. Inhibit 'em tour. Is it not helpful. Because the tumor has already evolved so much to be outside of 'em tours purview. Or is it it's actually harmful and that's of course separate right from the option. That could be helpful right so my understanding of the clinical literature in humans is that for most cancers cancer's once it's reached the point of diagnosis. That rapamycin is disappointing in its effectiveness not particularly effective. That's not true for all cancers answers but for most cancers it has not been as effective as you might expect given that we know that activation of 'em tour is common when you get high proliferation and the turning down or should stop that turn off so I think I think you're probably right. That at least part of the story is that one of the steps it's in the progression to cancer is evolving to ignore that signal to break a turning down. MTR 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 anticancer mechanism or certainly one of the most important anticancer mechanisms and we know that immune function goes down with age. That's probably one of the reasons. Why most cancers or age related so if you can boost age related immune function with rapamycin enhance immune surveillance? That's going to have a potent anticancer 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. You could permit amplifies. And there's not a lot of data yet so we did one study in My lab where we gave my. I think it's the highest dose that's ever been given in the context of aging to study. This was a daily injection of eight milligrams per kilogram. Plus we call it the party. Yeah right right and so this was a study where we only gave the mice rapamycin for three months so this was from twenty to twenty three months and then we stopped the treatment and what was interesting there was we got completely different effects in male mice versus female l. mice the male mice lived sixty percent longer after the end of treatment. They had better muscle function. They got cancer. The female mice had not difference in lifespan. The mice got rapamycin. Didn't get rapamycin 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 Rapamycin for three months all had aggressive support at cancers whereas about I think it was about thirty or forty percent of the vehicle treated mice so in black six. That's not an unusual. But but none of the rapamycin treated mice had non appointed cancers whereas like sixty percent of the mice. That didn't rapper myself. A two thousand nine study that kicked all this off. Actually Louis show a greater survival benefit in the female mice. Didn't that's right so I think again this gas because I don't actually have the data to back it up. My guess is that because we pushed the 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 or inhibitory effect. But that's one school of thought and I think that's right so at lower doses of the drug you see via bigger lifespan benefit in females than males. You repeat that experimented four megs per cake or something we haven't with we should so we did. Do I just need to tell you it. Pool of money just answer all 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 well and there. We saw increases in lifespan. Both males and females roughly the same magnitude. So it was that dose was nine times higher than what the ATP tested well so one the things. It'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 males. The gap has closed quite a bit so I think that females for whatever reason at a given concentration of rapamycin 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've pushed it to the point. Where rapamycin did something? Probably I believe the immune system that that allowed these immune cancers to to escape surveillance or become hyper proliferative and again. I'm not I'm not a cancer biologist. I'm not an immunologist so I don't I don't have a good feel for. What the mechanism is I can tell you what the observation is? And that's all of those animals had aggressive adequate cancer's when they got this three months of rapamycin just out of curiosity more be seller T.. Cell do you recall. I don't recall it's in the paper. We can look it up because there's an opportunity here 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 and really when you talk about like checkpoint inhibitors and things like that and it makes you wonder. Are there ways to make these things better. Maybe the check points the wrong example because you might get more auto immunity but but certainly you're talking about adoptive cell therapy anything. Anything that could boost either CD eight function or inhibit the rags or something. There might be ways almost makes you wonder if using rapamycin in in a different manner in combination with immune based therapy might make more sense. Yeah no I think there's a lot that could be done there for sure. Part of the reason why we haven't explored this discussed in more detail of one reason again as I said I'm not a cancer biologist. So it's not. It's not the thing I'm most interested and 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 translational about rapamycin as as drug in the context of aging my feeling Ling. Is that what we've uncovered here is not going to be relevant at the doses that we would think about giving too 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 about how effective those kinds of therapies are going to be in the elderly and maybe something like rapamycin could help could actually enhance the ability. Eddie of this. I mean this question. You posed when when David Sabatini Tim ferriss nabbed on Easter Island. Year ago. Over a year ago this might have been our favorite favorite mealtime discussion. Which is what best explains the increase in cancer incidence with age being in other words? What the primary primary driver be the reduction in immune surveillance or the length of time to accumulate mutations or the frequency of mutations like I mean it's not an obvious? CBS Aunts and I don't think it has to be just one. It's all those things. Yeah Yeah I certainly over. The last few years have come to think that the decline in immune the function is more important than I had initially thought that. That's my secretly. Want that to be the biggest driver because I think we have a better chance to control that and some of the other ones and I think it probably 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 stu you can actually deal with the mutation accumulation because your immune system is going to clear those Before they become problems. 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 professional healthcare services including the giving of medical advice and note. No doctor patient relationship is for 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 treat users should not disregard or Selena -taining 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 take conflicts of interest. Very seriously for all of my disclosures companies I invest in and advise please visit Peter Attiyah M._d.. Dot Com forward slash about.

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