Qualy #61 - Rapamycin in cancer treatment
Episode Stats
Words per Minute
188.35976
Summary
In this episode, we discuss whether rapamycin inhibits mTOR, which is a key anti-cancer agent, and whether it can be helpful or harmful in fighting cancer. We also talk about the role of aging in fighting disease, and the potential role of this agent in preventing cancer progression.
Transcript
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welcome to the qualies a subscriber exclusive podcast qualies is just a shorthand slang for
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a qualification round which is something you do prior to the race just a little bit quicker
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subscribe so without further delay i hope you enjoy today's quali and so there's really two different
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questions the first would be if you take a patient with cancer and you inhibit mTOR is it not helpful
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because the tumor has already evolved so much to be outside of mTOR's purview or is it it's actually
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harmful and that's of course separate from the option that it could be helpful right so my understanding
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of the clinical and the literature in humans is that for most cancers once it's reached the point
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of diagnosis that rapamycin is disappointing in its effectiveness it's not particularly effective
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that's not true for all cancers but for most cancers it has not been as effective as you might
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expect given that we know that activation of mTOR is common when you get high proliferation and
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turning down mTOR should stop that turn off a proliferative cell so i think i think you're probably
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right that at least part of the story is that one of the steps in the progression to cancer is evolving
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to ignore that signal the break yeah of turning down mTOR so rapamycin may not be effective there
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i think it's a complicated system though because the effects of rapamycin on the immune system
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could have beneficial effects in terms of cancer or detrimental effects so we know that immune
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surveillance is probably the most important anti-cancer mechanism or certainly one of the most
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important anti-cancer mechanisms and we know that immune function goes down with age that's probably
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one of the reasons why most cancers are age related so if you can boost age related immune function
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with rapamycin in enhance immune surveillance that's going to have a potent anti-cancer mechanism
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and again this is my guess my guess is that's why we see in the studies in mice that cancers are
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pushed back during aging by rapamycin on the other hand if the dose of rapamycin is high enough
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that you're actually inhibiting immune function that could be that could promote answers yeah and
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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
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dose that's ever been given in the context of an aging study this was a daily injection of eight
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milligrams per kilogram so that's we call it the party dose yeah right right and so this was a study
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where we only gave the mice rapamycin for three months so this was from 20 to 23 months and then we
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stopped the treatment and what was interesting there was we got completely different effects in
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male mice versus female mice the male mice lived 60 longer after the end of treatment they had better
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muscle function they got less cancer the female mice had no difference in lifespan the mice that got
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rapamycin or didn't get rapamycin but they died with i want to say from but it's hard to say for sure
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what a mouse dies from they died with very different types of cancers so the female mice that had gotten
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this high dose of rapamycin for three months all had aggressive hematopoietic cancers whereas about
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i think it was about 30 or 40 percent of the vehicle treated mice so in black six that's not an uncommon
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cancer to get but none of the rapamycin treated mice had non-hematopoietic cancers whereas like 60
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percent of the mice that didn't get rapamycin now the 2009 study that kicked all this off actually
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showed a greater survival benefit in the female mice didn't it that's right so i think and again
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this is a guess because i don't actually have the data to back it up my guess is that because we pushed
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the dose so high we might have actually taken it too far in the female so one school of thought is that
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female mice at least we don't know if this is true in any other organism female mice are more sensitive
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to rapamycin and that could either be that they don't clear the drug as quickly or that for whatever
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reason in female mice the same amount of rapamycin has a greater mTOR inhibitory effect but that's one
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school of thought and i kind of think that's right so at lower doses of the drug you see a bigger
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lifespan benefit in females than in males did you repeat that experiment at like four mgs per kg or
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something different we haven't we haven't with we should so we did do we just need an infinite pool
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of money i agree to do all of these like just answer all these figure out the most important
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questions yeah and i think the dose response is really important we did do a lower dose for three
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months as well and there we saw increases in lifespan in both males and females roughly the same
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magnitude so it was that dose was nine times higher than what the itp tested wow so one of the things
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that's interesting though is as you go higher in dose so three times higher than what they originally
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tested the females still live a little bit longer but the difference between males and females
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the gap has closed quite a bit so i think that females for whatever reason at a given concentration
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of rapamycin are just more affected by that amount of the drug and i think what we did in our
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high dose study is we just pushed it a little too far we pushed it to the point where rapamycin did
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something probably to the immune system that that allowed these immune cancers to to escape surveillance or
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become hyper proliferative and again i'm not i'm not a cancer biologist i'm not an immunologist so i
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don't i don't have a good feel for what the mechanism is i can tell you what the observation
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is and that's that all of those animals had aggressive hematopoietic cancers when they got
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this three months of rapamycin just out of curiosity more b cell or t cell do you recall i don't recall
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it's in the paper we could look it up because there's an opportunity here to do the reverse right i mean
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there's an opportunity to take right now we're seeing just an unbelievable amount of activity in
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adoptive cell therapy and or even when you just talk about like checkpoint inhibitors and things
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like that like it makes you wonder are there ways to make these things better maybe the checkpoint's
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the wrong example because you might get more autoimmunity but but certainly when you talk about
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adoptive cell therapy anything that could boost either you know cd8 function or inhibit the regs or
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something there might be ways like it almost makes you wonder if using rapamycin in a different manner
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in combination with immune-based therapies might make more sense yeah no i think there's a lot that
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could be done there for sure part of the reason why we haven't explored this in more detail well one
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reason is again as i said i'm not a cancer biologist so it's not that's not the thing i'm most interested in
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i think it's really interesting biology but it's not the thing i'm most interested in but i also feel
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like because the dose that we gave was so high that again thinking translationally about rapamycin as
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as a drug in the context of aging my feeling is that what we've uncovered here is not going to be
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relevant at the doses that we would think about giving to yeah yeah yeah yeah so that's why i haven't
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really spent a lot of my time trying to figure out what's going on there but i think certainly in the
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context of cancer immune therapies i think we do need to think a little bit more about how effective
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those kinds of therapies are going to be in the elderly and maybe something like rapamycin could
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help could actually enhance the ability of those therapies i mean this question you posed when when
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david sabatini tim ferris and nap chandel and i were in easter island a year ago over a year ago this
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might have been our favorite mealtime discussion which is what best explains the increase in cancer
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incidence with age being in other words what would the primary driver be the reduction in immune
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surveillance or the length of time to accumulate mutations or the frequency of mutations like i mean
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yeah it's not an obvious answer and i don't think it has to be just one no exactly it's almost all
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those things are working together yeah yeah yeah i certainly over the last few years have come to
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think that the decline in immune function is it's certainly more important than i had initially
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thought that that's my i mean i secretly want that to be the biggest driver because i think we have a
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better chance to control that yeah than some of the other ones and i think it probably is that would
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be my guess and i and i also think it kind of makes sense that if you have an immune system that's
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functioning the way it's supposed to you can actually deal with the mutation accumulation because
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your immune system is going to clear those before they become yeah problems i hope you enjoyed today's
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