Cancer is not one thing, it's a huge zoo of many many many ways that cells start to break the social contract and divide in an uncontrolled manner.
One of the most commonly observed broken mechanisms is mutation in the gene KRAS that turns this on/off growth switch into the permanently on position.
This has been known for decades, of course. And there have been huge amounts of effort to try to develop drugs that target KRAS in cancer, but for decades it's always been thought of as 'undruggable' because of the difficulty of finding any molecules that would affect it.
This new drug, that finally treats KRAS mutated cancers, goes about it in a new way. Instead of trying to gum up the works of a single protein by sticking a small chemical in it, it effectively "glues" the KRAS protein to another protein, CypA, which keeps the switch away from reaching the normal areas where it's "on switch" activity works.
So this new drug means two things: 1) a lot of the most difficult to treat cancers are now far more treatable, and in the next 1-5 years clinical trials will tell us which cancers this particular drug works well for, 2) there's an entire new class of drug activity that everybody is chasing at this very moment, so in 5-25 years we'll likely have a huge number more of these sorts of treatments.
How does it avoid targeting KRAS in healthy cells? Or is this another form of chemotherapy where we're trying our hardest to deliver the right amount of poison that kills the cancer before it kills the rest of you?
It doesn't. Cancerous cells have a much higher dependency on RAS signaling to survive, so it's a drug that kills everything that's replicating via RAS signaling, much like standard chemotherapy kills cells in general that are reproducing more quickly.
However this is just the first version of the drug, it can be combined with other modalities to allow more selective targeting of cancer versus not cancer cells (e.g antibody-drug conjugation). And when used in earlier stage cancers, rather than the advanced cancers in this first clinical trial, there's the possibility of lower dosing that has less strong side effects.
This is just the first attack that has ever broken through to hit a key weakness of some cancers. It's the start of learning, a breakthrough that will launch refinements, enhancements, and a ton of innovation. That sort of innovation is sometimes derided as "me-too" drugs, and not meaningful, but some of the biggest advancements in cancer care have been from taking very hard to tolerate treatments and making them more tolerable and refined and better for patients, allowing longer and more thorough killing of cancer cells. I would expect we will see a lot of that here, as well as work towards combinations with other drugs.
This drug targets cells with a KRAS mutation that locks the KRAS switch in the ON state, driving uncontrolled growth. Cells with this mutation are abnormal and predisposed to becoming cancer ... so by definition are not healthy.
>a lot of the most difficult to treat cancers are now far more treatable, and in the next 1-5 years clinical trials will tell us which cancers this particular drug works well for,
Can you help disambiguate this? Are there treatments now, or are there potential treatments with trials in 1-5 years?
The next 1-5 years will tell us which cancers this new drug will work well on, right now it's only been tried in pancreatic cancer when people have failed their first treatment. The new drug from the article, daroxonrasib, has nine trials i see currently, here:
The first two are the trial that just completed and showed success: people that have pancreatic cancer that failed other treatments, then a "trial" that is meant to give quick access to more people now that it's been shown to work.
Then there's a trial for using it as the first-line treatment for pancreatic cancer, one for lung cancer (NSCLC), and also various combinations with other drugs. I expect we'll see a ton of new trials registered in the coming year. Especially something in combination with colon cancer, because a common drug resistance mechanism in colon cancer is to develop KRAS mutation.
The thing is that we don't really know which cancers it will work well in until we try. And there's limited number of people with cancer that enter clinical trials, and we want to give each person their very best chance at survival, and then there's the massive expense of running the clinical trial itself, so learning happens slowly, one month of survival at a time, or one cancer recurrence at a time, or one death at a time. Patients that take part in clinical trials really are the heroes here. (Especially with the side effects of this new drug, which are horrible. It is a revolutionary drug, but we need to learn how to manage the other things it does as well, and that's going to take time.)
I think the meaning is that because we can see success with KRAS mutation of pancreatic cancer, we can now begin clinical trials for other cancers that may have KRAS mutation (colorectal, lung) and see if there is success there. If there is success in treating other cancers during clinical trials, it could be fast tracked through FDA to be more generally available and then become part of the national treatment option (ideally in 1-5 years after clinical trials).
Yes, and one of the hallmarks of cancer is a removal of the usual DNA damage checkpoints. Cells have sensors that detect damaged DNA and stop cell division, and once that is gone evolution happens on an extremely accelerated times scale. In lung cancer, for example, we have developed entire series of drugs to go after successive resistance mutations inside the EGFR gene.
When we first started getting good at sequencing the DNA of tumors, I remember initial reports of taking samples across the 3D space of a tumor and finding great spatial heterogeneity in the tumor genomes.
I'm actually most excited for using this drug in combination with colon cancer, where KRAS mutation is a common drug resistance evolution in response to drugs that target the gene EFGR (though cancer researchers may all have their favorites to go after, colon cancer went after my family especially hard).
Absolutely, this is selective pressure at work on cells with malregulated genetics. Most typically, this is in the form of drug efflux pumps, but you can definitely get more specific resistances.
Ways to avoid specific resistance include multiple treatments simultaneously, since the probability of generating resistance to both is the product of the probability of resistance either.
evolution is a wrong concept to approach it. cancer is not a separate life form, but a bug in the regeneration system of a complicated life form. it doesn’t exist outside of it, it cannot propagate.
The golden panacea for this would be a gene editing mechanism that will work in every cell in the body. Once we have something we can do whole hog gene replacement, most human health problems would be solved forever.
For every cell mechanism that's being abused by cancer to fuel its growth, there are other cells in the body for which that mechanism is crucial for their correct functioning. Wholesale editing every cell in the body mostly guarantees that the patient does not die of cancer -- the cure will kill them before the disease does.
I don't much care what happens to most inmates but those with really long sentences should probably not be released early (or at all!) because they pose too much of a risk to the rest of us.
I know this is a popular "well actually" to do, but it is not always useful in a conversation. Yes, all cancers are different, but yes, cancer is also one thing: unchecked, harmful division of cells.
Bacteria are also all different, but still they are "one thing", and despite their diversity, antibiotics exist that can deal with many species of them at once. It is reasonable to talk about bacteria and antibacterial medications, it is also reasonable to talk about cancer and cancer treatment. I truly hope cancer will meet its "penicillin" one day (yes I know this is unlikely).
It seems relevant here because the question was “How will this potentially help me if I get cancer?” and the answer is “Not at all unless you get a particular form of cancer that this applies to”.
> Bacteria are also all different, but still they are "one thing", and despite their diversity, antibiotics exist that can deal with many species of them at once.
Except people don’t ask “what if I get bacteria” the way they ask about cancer. If the story was about a new antibiotic that only affected 20% of common infectious bacteria strains and someone asked “in laypersons terms, how will this help me if I get a bacterial infection”, it would be appropriate to clarify that it only applies to some bacteria.
I understand where you are coming from here, but I think it is helpful for people to overtly grasp that there are very different cancers, very different treatments, and indeed very different outcomes.
Without this understanding it becomes a quick jump from "we're spending all this money on cancer" to "we've made no progress"
An example of the nuance plays out in the common cancers (like breast and prostrate). These have between 90 and 100% 5 year survival rates. Others (like the one in this article, pancreatic) have very poor survivability.
As you note, it's very unlikely that we'll "cure cancer". But we already "cure" (for some definition of cure) some cancers. Progress is slow, methodical, and incremental. It can feel like a lost cause when viewed from afar, but up close very real progress is being made. And that's an important message to pass along.
The correct way to read the sentence is “all cancers do not have the same causal mechanism” but people don’t talk like that because it’s off putting. Language is fluid and it’s generally on the reader to infer meaning from context. If we can do so reasonably, we do it, and we don’t need to then write additional posts chiding people over an interpretation that’s highly unlikely to be the intended one. I don’t mean to be pushy about this, btw. It’s just that pedantry can be valuable, but only if it isn’t abused.
Cancer cells, by definition, are not a uniform mass. It will depend on the cancer type, which in turn is defined by the properties those cells have. And mutations happen all the time, often more in cancer cells when their repair systems also have mutations, e. g. are less efficient. By that definition alone, there can never be a wonder-cure for all cancer types. At best you can find some proteins more important (p53 for instance) and while more than 50% of cancer cells have some form of mutation in p53, others simply don't. By that definition there will never be a penicillin-equivalent to all cancer types.
It won't help... mind you this is an article from the economist. There is no such thing as a cancer "master switch", that would equal a disease master switch and that point we have solved biology.
Cancer is not one thing, it's a huge zoo of many many many ways that cells start to break the social contract and divide in an uncontrolled manner.
One of the most commonly observed broken mechanisms is mutation in the gene KRAS that turns this on/off growth switch into the permanently on position.
This has been known for decades, of course. And there have been huge amounts of effort to try to develop drugs that target KRAS in cancer, but for decades it's always been thought of as 'undruggable' because of the difficulty of finding any molecules that would affect it.
This new drug, that finally treats KRAS mutated cancers, goes about it in a new way. Instead of trying to gum up the works of a single protein by sticking a small chemical in it, it effectively "glues" the KRAS protein to another protein, CypA, which keeps the switch away from reaching the normal areas where it's "on switch" activity works.
So this new drug means two things: 1) a lot of the most difficult to treat cancers are now far more treatable, and in the next 1-5 years clinical trials will tell us which cancers this particular drug works well for, 2) there's an entire new class of drug activity that everybody is chasing at this very moment, so in 5-25 years we'll likely have a huge number more of these sorts of treatments.
How does it avoid targeting KRAS in healthy cells? Or is this another form of chemotherapy where we're trying our hardest to deliver the right amount of poison that kills the cancer before it kills the rest of you?
It doesn't. Cancerous cells have a much higher dependency on RAS signaling to survive, so it's a drug that kills everything that's replicating via RAS signaling, much like standard chemotherapy kills cells in general that are reproducing more quickly.
However this is just the first version of the drug, it can be combined with other modalities to allow more selective targeting of cancer versus not cancer cells (e.g antibody-drug conjugation). And when used in earlier stage cancers, rather than the advanced cancers in this first clinical trial, there's the possibility of lower dosing that has less strong side effects.
This is just the first attack that has ever broken through to hit a key weakness of some cancers. It's the start of learning, a breakthrough that will launch refinements, enhancements, and a ton of innovation. That sort of innovation is sometimes derided as "me-too" drugs, and not meaningful, but some of the biggest advancements in cancer care have been from taking very hard to tolerate treatments and making them more tolerable and refined and better for patients, allowing longer and more thorough killing of cancer cells. I would expect we will see a lot of that here, as well as work towards combinations with other drugs.
This drug targets cells with a KRAS mutation that locks the KRAS switch in the ON state, driving uncontrolled growth. Cells with this mutation are abnormal and predisposed to becoming cancer ... so by definition are not healthy.
>a lot of the most difficult to treat cancers are now far more treatable, and in the next 1-5 years clinical trials will tell us which cancers this particular drug works well for,
Can you help disambiguate this? Are there treatments now, or are there potential treatments with trials in 1-5 years?
The next 1-5 years will tell us which cancers this new drug will work well on, right now it's only been tried in pancreatic cancer when people have failed their first treatment. The new drug from the article, daroxonrasib, has nine trials i see currently, here:
https://clinicaltrials.gov/search?intr=daraxonrasib&viewType...
The first two are the trial that just completed and showed success: people that have pancreatic cancer that failed other treatments, then a "trial" that is meant to give quick access to more people now that it's been shown to work.
Then there's a trial for using it as the first-line treatment for pancreatic cancer, one for lung cancer (NSCLC), and also various combinations with other drugs. I expect we'll see a ton of new trials registered in the coming year. Especially something in combination with colon cancer, because a common drug resistance mechanism in colon cancer is to develop KRAS mutation.
The thing is that we don't really know which cancers it will work well in until we try. And there's limited number of people with cancer that enter clinical trials, and we want to give each person their very best chance at survival, and then there's the massive expense of running the clinical trial itself, so learning happens slowly, one month of survival at a time, or one cancer recurrence at a time, or one death at a time. Patients that take part in clinical trials really are the heroes here. (Especially with the side effects of this new drug, which are horrible. It is a revolutionary drug, but we need to learn how to manage the other things it does as well, and that's going to take time.)
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I think the meaning is that because we can see success with KRAS mutation of pancreatic cancer, we can now begin clinical trials for other cancers that may have KRAS mutation (colorectal, lung) and see if there is success there. If there is success in treating other cancers during clinical trials, it could be fast tracked through FDA to be more generally available and then become part of the national treatment option (ideally in 1-5 years after clinical trials).
That was a really good summary, thank you.
Can we end up with a situation like antimicrobial resistance, where cancer itself evolves to resist these new treatments?
Yes, and one of the hallmarks of cancer is a removal of the usual DNA damage checkpoints. Cells have sensors that detect damaged DNA and stop cell division, and once that is gone evolution happens on an extremely accelerated times scale. In lung cancer, for example, we have developed entire series of drugs to go after successive resistance mutations inside the EGFR gene.
When we first started getting good at sequencing the DNA of tumors, I remember initial reports of taking samples across the 3D space of a tumor and finding great spatial heterogeneity in the tumor genomes.
I'm actually most excited for using this drug in combination with colon cancer, where KRAS mutation is a common drug resistance evolution in response to drugs that target the gene EFGR (though cancer researchers may all have their favorites to go after, colon cancer went after my family especially hard).
Absolutely, this is selective pressure at work on cells with malregulated genetics. Most typically, this is in the form of drug efflux pumps, but you can definitely get more specific resistances.
Ways to avoid specific resistance include multiple treatments simultaneously, since the probability of generating resistance to both is the product of the probability of resistance either.
evolution is a wrong concept to approach it. cancer is not a separate life form, but a bug in the regeneration system of a complicated life form. it doesn’t exist outside of it, it cannot propagate.
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thats environmental evolution...what happens here is cell "evolution" within a specific body
Thanks for the explanation!
The golden panacea for this would be a gene editing mechanism that will work in every cell in the body. Once we have something we can do whole hog gene replacement, most human health problems would be solved forever.
For every cell mechanism that's being abused by cancer to fuel its growth, there are other cells in the body for which that mechanism is crucial for their correct functioning. Wholesale editing every cell in the body mostly guarantees that the patient does not die of cancer -- the cure will kill them before the disease does.
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[flagged]
I don't much care what happens to most inmates but those with really long sentences should probably not be released early (or at all!) because they pose too much of a risk to the rest of us.
I have an even better proposal.
We'll just use you!
Are you going to give them cancer first too?
This is a horrifying proposal not only on the ethics front but also in the scientific uselessness of it.
This is exactly the type of thing that gave the Nazis the bad name they deserve.
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> Cancer is not one thing,
I know this is a popular "well actually" to do, but it is not always useful in a conversation. Yes, all cancers are different, but yes, cancer is also one thing: unchecked, harmful division of cells.
Bacteria are also all different, but still they are "one thing", and despite their diversity, antibiotics exist that can deal with many species of them at once. It is reasonable to talk about bacteria and antibacterial medications, it is also reasonable to talk about cancer and cancer treatment. I truly hope cancer will meet its "penicillin" one day (yes I know this is unlikely).
It seems relevant here because the question was “How will this potentially help me if I get cancer?” and the answer is “Not at all unless you get a particular form of cancer that this applies to”.
> Bacteria are also all different, but still they are "one thing", and despite their diversity, antibiotics exist that can deal with many species of them at once.
Except people don’t ask “what if I get bacteria” the way they ask about cancer. If the story was about a new antibiotic that only affected 20% of common infectious bacteria strains and someone asked “in laypersons terms, how will this help me if I get a bacterial infection”, it would be appropriate to clarify that it only applies to some bacteria.
5 replies →
I understand where you are coming from here, but I think it is helpful for people to overtly grasp that there are very different cancers, very different treatments, and indeed very different outcomes.
Without this understanding it becomes a quick jump from "we're spending all this money on cancer" to "we've made no progress"
An example of the nuance plays out in the common cancers (like breast and prostrate). These have between 90 and 100% 5 year survival rates. Others (like the one in this article, pancreatic) have very poor survivability.
As you note, it's very unlikely that we'll "cure cancer". But we already "cure" (for some definition of cure) some cancers. Progress is slow, methodical, and incremental. It can feel like a lost cause when viewed from afar, but up close very real progress is being made. And that's an important message to pass along.
2 replies →
The problem is the similarities of cancer to normal cells. We have penicilin that works against all human cells. We call that poison.
Now, "no, i mean poisons that attack the special chemistry of cancer," oh yes, those we call chemo.
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The correct way to read the sentence is “all cancers do not have the same causal mechanism” but people don’t talk like that because it’s off putting. Language is fluid and it’s generally on the reader to infer meaning from context. If we can do so reasonably, we do it, and we don’t need to then write additional posts chiding people over an interpretation that’s highly unlikely to be the intended one. I don’t mean to be pushy about this, btw. It’s just that pedantry can be valuable, but only if it isn’t abused.
> I truly hope cancer will meet its "penicillin" one day (yes I know this is unlikely).
Penicillin blocks a specific enzyme (transpeptidase).
https://en.wikipedia.org/wiki/Penicillin-binding_proteins
Cancer cells, by definition, are not a uniform mass. It will depend on the cancer type, which in turn is defined by the properties those cells have. And mutations happen all the time, often more in cancer cells when their repair systems also have mutations, e. g. are less efficient. By that definition alone, there can never be a wonder-cure for all cancer types. At best you can find some proteins more important (p53 for instance) and while more than 50% of cancer cells have some form of mutation in p53, others simply don't. By that definition there will never be a penicillin-equivalent to all cancer types.
Benign cancers are a thing. They might not kill like they show in the Hollywood movies, but your quality of life will be significantly diminished.
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You've been downvoted but I would say you are right. It would be more accurate to say "cancer does not have one cause".
It won't help... mind you this is an article from the economist. There is no such thing as a cancer "master switch", that would equal a disease master switch and that point we have solved biology.
What do you mean “it won’t help”?
It most likely will help if you get pancreatic cancer. It might help if you get one of the other types of cancers with this mutation.
And it will likely lead to new treatments for some of the worst kinds of cancer.
One of the many therapies that are being developed so that you can survive longer even with the most lethal tumours.