7 ms·

A Cancer ‘Moonshot’ Needs Big Data

49 points by aficionado 11y ago

sjg007 11y ago
More importantly, we need FDA regulatory reform. There is absolutely no reason that approved anti-cancer drugs in one cancer type and stage should be limited to just those cases. You should be able to spin up a direct Phase II study without going through Phase I. And more importantly you should be able to get these drugs when all other options are exhausted. People need to read the book "The Death of Cancer" by the former NCI chief Vincent DeVita. I agree that we need a cancer czar and that the NCI needs to run the show including drug approvals. In addition, academia needs to get with the program.
- OopsCriticality 11y ago
  > There is absolutely no reason that approved anti-cancer drugs in one cancer type and stage should be limited to just those cases. Can you expand on that?
  - chrisamiller 11y ago
    Mutations in the BRAF gene, to name one druggable example, are a cause of many different types of cancer - melanoma, some breast, small-cell lung cancer, etc. Under the current paradigm, each type of cancer is treated as a different disease and requires a different clinical trial. This is bad. What should happen (and is beginning to happen, with "basket trials") is that cancers are grouped by their genetic profile, instead of their tissue of origin. The BRAF V600E mutation is targetable with Vemurafenib, and so that drug should be used regardless of whether you have breast cancer or lung cancer.
    - niels_olson 11y ago
      Perhaps, but it is also true that these targeted therapies have different success rates among different cancers. Vemurafenib, famously approved for melanoma, hasn't been as successful in papillary thyroid.
    - OopsCriticality 11y ago
      Certainly it makes sense to consider genetic profile in treatment, but doesn't the statement "that drug should be used regardless of whether you have breast cancer or lung cancer" ignore the local tumor microenvironment and possible differences in drug resistance expression between cell types, i.e., isn't reducing cancer down to genetic profile alone potentially as problematic as reducing cancer down to its tissue of origin?
      - chrisamiller 11y ago
        Your points are right on - I oversimplified while trying to explain the concept.
    - dnautics 11y ago
      This isn't really that much of an issue because oncologists are not always idiots and can prescribe drugs off-label, with cause. Identifying a braf mutant in a disparate cancer type would probably qualify.
      - sjg007 11y ago
        It is a huge issue. They risk FDA censure and it usually requires IRB approval as well. It will change with precision medicine but it won't change fast enough. People really need to read DeVita's book. All of my comments are taken from his arguments. DeVita was the chief of the NCI for 30 years.
- deleted 11y ago
  [deleted]
- chrisamiller 11y ago
  I'm sorry that you think academia isn't "with the program". There's lots of great basic and translational research going on in the academic sphere. Can you at least elaborate, if you're going to paint us all with a broad brush?
  - sjg007 11y ago
    Academic cancer centers need to focus on improving clinical outcomes, not just basic research. That cancer centers are associated with primary research institutions universities is largely a compromise between with the NIH and the NCI when the national cancer act was implemented. Tenure is based on basic research publications and on not clinical trials. So therapies are not optimized.
    - 88e282102ae2e5b 11y ago
      How are we supposed to cure diseases we don't fully understand? How can radical new solutions be tested if we don't even know if they're feasible? Basic research answers these questions.
      - sjg007 11y ago
        If you would have waited until you fully understood a disease in order to treat it then kids would still be dying of leukemia today instead of having a 90% remission rate today. People should read about Emil Freireich and the development of chemotherapy.
        nonbel 11y ago
        >"kids would still be dying of leukemia today instead of having a 90% remission rate today" Do you know a good source for the historical data? I am wondering how they rule out that in the 1950s/60s they saw only much sicker patients, while today a bigger population gets diagnosed and treated. Related, there may be lead time bias: https://en.wikipedia.org/wiki/Lead_time_bias https://en.wikipedia.org/wiki/Lead_time_bias Any source with discussion of these methodological issues would be helpful.
- danieltillett 11y ago
  What we need to do is get the price down of cancer drug development. The fundamental problem is cancer is really many diseases so that any targeted drug will only be specific for a very small subset of cancers. This means the market for any new targeted drug is very small and so the ludicrous cost of bring as new drug to market is too great to be supported by the small number of people that will use it. The cost of these new targeted drugs is basically too high for any healthcare system to support, but the we need to make the drugs even more specific if we are going to get all the cancer types. Smaller and smaller market with every rising development costs = failure.
- randcraw 11y ago
  Simply eliminating Phase I is the wrong solution. Entering a Phase II study before Phase I is a great way to maim or kill people. Anti-cancer drugs are often severely toxic; even the new spate of immunocentric therapies proved highly dangerous when first administered. Several early recipients died due to clueless drug administration protocols. THAT's the reason we have Phase I. Humans usually respond differently to a drug than the animals who have gone before. That said, I think the FDA should approach cancer differently than other diseases, probably by establishing a new experimental model entirely (eliminating the Phase I/II/III system). Given that canger drugs and patients and protocols must ALWAYS be administered sensitively, circumstantially, and adaptively, the current 3 phase system seems to be serving cancer patients poorly, locking them into ineffective treatments for too long, based on too much emphasis on inflexible trial policy. Experimental protocols that are more adaptive and personalized are needed. Of course, this will be very hard technically and insanely expensive clinically. How to begin this? Like Obama, I'd love to see a 'moon shot' reinvention of the cancer business. Perhaps a project-based redesign of the system is possible, by engaging the most innovative cancer research clinicians and data analysts to explore alternative models for cancer research and drug trials. If that's what Obama has in mind, I support his wish. Now how do we make it work?
  - sjg007 11y ago
    I meant in cases where the drug is already FDA approved e.g. Phase I trial has already been completed in other cancer types. There is no need to do another Phase I trial just because it is another cancer type. The restrictions on using an approved drug for a new cancer type or stage is silly. The original NCI program for treating Leukemias worked pretty well. The FDA is extremely risk adverse which is not what you want for terminal cancer treatment.
fallous 11y ago
"Cancer" isn't a single disease or problem domain, but what could be categorized as a syndrome that shares some basic commonalities. The governmental "War on Cancer" began under Nixon and was pitched as a "moonshot" type of program, which promptly ran aground on the realities of cancers. If only there were some sort of documentation for this kind of effort... perhaps they could call it "The Emperor of All Maladies" or something.
- Outdoorsman 11y ago
  Excellent PBS documentary you ironically refer to... http://www.pbs.org/show/story-cancer-emperor-all-maladies/ http://www.pbs.org/show/story-cancer-emperor-all-maladies/ Quite a beast to conquer, for the reason you stated...errant DNA replication, probably the single most powerful software on Earth, gone beserk... Obama's "moonshot" reference likely refers to a proposed attempt at re-centralizing the efforts of earlier research projects, to consolidate and benefit from known gains... "Moonshot" is probably simply the hyperbole choice of a speechwriter, designed to inflate the magnitude and importance of the endeavor...
  - adenadel 11y ago
    The book is excellent as well http://www.amazon.com/Emperor-All-Maladies-Biography-Cancer/dp/1439170916/ http://www.amazon.com/Emperor-All-Maladies-Biography-Cancer/...
    - ggreer 11y ago
      For those interested in reading this book: Your mileage may vary. I wanted to like it, but I couldn't get over the writing. It had so many flourishes and unnecessary descriptions that I stopped reading halfway through.
- nonbel 11y ago
  >'"Cancer" isn't a single disease or problem domain, but what could be categorized as a syndrome that shares some basic commonalities.' Cancer is characterized by having cells with an abnormal number of chromosomes and genetic instability. It is one disease. I don't know the origins of it, but this "many disease" claim sounds like an excuse for lack of progress in targeting aneuploid cells. "In contrast to normal cells, aneuploidy--alterations in the number of chromosomes--is consistently observed in virtually all cancers." https://www.ncbi.nlm.nih.gov/pubmed/15549096 https://www.ncbi.nlm.nih.gov/pubmed/15549096
chrisamiller 11y ago
I don't agree with much that Tom Coburn says, but he's right that 'data silos' are a big problem in cancer research. To elaborate on a few points: - While enrolling 500 people with breast cancer in a study might be easy enough at one academic hospital, there are lots of rare cancer types. It's fiendishly hard to gather enough cases to do real research on these, and samples are like gold, so people are resistant to sharing. - There's lots of duplication of effort. While studies funded by the NIH are required to deposit their data, what's being deposited is raw sequence data, which requires lots of computation, disk, and skill to turn back into useful information about the mutations in cancer. - The clinical data (phenotype) that is released with studies is often incomplete or vague enough to be useless - Getting data into and out of these access-controlled repositories is, to put it mildly, a pain in the ass. We do need to protect people's privacy, but removing some of these hurdles would go a long way towards accelerating the field.
downunder 11y ago
I think we should be talking about 'uranushots' rather than moonshot because 1. the moon is close and now relatively ho-hum while uranus is in another category altogether; 2. For these things to happen a little good luck is required.
- deleted 11y ago
  [deleted]
aaronmck 11y ago
Well, better / more uniform access to patient records would be nice, but more money into basic research is probably the best bet (as it has always been). It makes me think of this Gregory Petsko commentary (open access): http://www.genomebiology.com/2001/3/1/comment/1001 http://www.genomebiology.com/2001/3/1/comment/1001 With the great quote: "...If a hundred years of cancer research has taught us anything, it is that if you must get cancer, you want to be a mouse, because we can cure cancer in mice."
- nonbel 11y ago
  "...If a hundred years of cancer research has taught us anything, it is that if you must get cancer, you want to be a mouse, because we can cure cancer in mice." Maybe it is cheaper to keep trying and there is less oversight so more BS gets through...
- danieltillett 11y ago
  >”...because we can cure cancer in mice.” Actually as far as I know we can’t cure mice of cancer - by cancer I mean natural cancers that mice get as they age just like human cancers. I have looked through the literature in great detail and I can’t find a single recent paper where anyone has even tried curing mice of cancer. If anyone know of one I would love to read it. The way we go about trying to cure cancer is insane. We basically take inbred mice, inject them with a cancer cell line to give them cancer, and then treat them with experimental drug X. This process is nothing like how real human cancers arise. On top of this we only test new drugs in people that have failed all other treatments and have very high tumour burdens. We then demand that the new drug have a significant effect in these patients despite us needing drugs that work in newly diagnosed patients. If we get a drug that works it is more by chance than design.
  - nonbel 11y ago
    >"I have looked through the literature in great detail and I can’t find a single recent paper where anyone has even tried curing mice of cancer." It's interesting how your perspective will change after reading the literature. It is the same thing with the various mutations claimed to cause cancer. For example, in this thread someone claims mutations to BRAF cause cancer. I am nearly certain that inspecting the literature will not result in any studies where that gene in a normal cell was mutated, and then it took on the properties of a cancer cell. Maybe we will see some data on many cell generations later and in conjunction with various other treatments, but not the direct experiment of "non-cancer cell + BRAF mutation = cancer cell" while "non-cancer ell + control treatment = non-cancer cell".

49 points by aficionado 11y ago

More importantly, we need FDA regulatory reform. There is absolutely no reason that approved anti-cancer drugs in one cancer type and stage should be limited to just those cases. You should be able to spin up a direct Phase II study without going through Phase I. And more importantly you should be able to get these drugs when all other options are exhausted. People need to read the book "The Death of Cancer" by the former NCI chief Vincent DeVita. I agree that we need a cancer czar and that the NCI needs to run the show including drug approvals. In addition, academia needs to get with the program.

OopsCriticality 11y ago
> There is absolutely no reason that approved anti-cancer drugs in one cancer type and stage should be limited to just those cases. Can you expand on that?
- chrisamiller 11y ago
  Mutations in the BRAF gene, to name one druggable example, are a cause of many different types of cancer - melanoma, some breast, small-cell lung cancer, etc. Under the current paradigm, each type of cancer is treated as a different disease and requires a different clinical trial. This is bad. What should happen (and is beginning to happen, with "basket trials") is that cancers are grouped by their genetic profile, instead of their tissue of origin. The BRAF V600E mutation is targetable with Vemurafenib, and so that drug should be used regardless of whether you have breast cancer or lung cancer.
  - niels_olson 11y ago
    Perhaps, but it is also true that these targeted therapies have different success rates among different cancers. Vemurafenib, famously approved for melanoma, hasn't been as successful in papillary thyroid.
  - OopsCriticality 11y ago
    Certainly it makes sense to consider genetic profile in treatment, but doesn't the statement "that drug should be used regardless of whether you have breast cancer or lung cancer" ignore the local tumor microenvironment and possible differences in drug resistance expression between cell types, i.e., isn't reducing cancer down to genetic profile alone potentially as problematic as reducing cancer down to its tissue of origin?
    - chrisamiller 11y ago
      Your points are right on - I oversimplified while trying to explain the concept.
  - dnautics 11y ago
    This isn't really that much of an issue because oncologists are not always idiots and can prescribe drugs off-label, with cause. Identifying a braf mutant in a disparate cancer type would probably qualify.
    - sjg007 11y ago
      It is a huge issue. They risk FDA censure and it usually requires IRB approval as well. It will change with precision medicine but it won't change fast enough. People really need to read DeVita's book. All of my comments are taken from his arguments. DeVita was the chief of the NCI for 30 years.
deleted 11y ago
[deleted]
chrisamiller 11y ago
I'm sorry that you think academia isn't "with the program". There's lots of great basic and translational research going on in the academic sphere. Can you at least elaborate, if you're going to paint us all with a broad brush?
- sjg007 11y ago
  Academic cancer centers need to focus on improving clinical outcomes, not just basic research. That cancer centers are associated with primary research institutions universities is largely a compromise between with the NIH and the NCI when the national cancer act was implemented. Tenure is based on basic research publications and on not clinical trials. So therapies are not optimized.
  - 88e282102ae2e5b 11y ago
    How are we supposed to cure diseases we don't fully understand? How can radical new solutions be tested if we don't even know if they're feasible? Basic research answers these questions.
    - sjg007 11y ago
      If you would have waited until you fully understood a disease in order to treat it then kids would still be dying of leukemia today instead of having a 90% remission rate today. People should read about Emil Freireich and the development of chemotherapy.
      - nonbel 11y ago
        >"kids would still be dying of leukemia today instead of having a 90% remission rate today" Do you know a good source for the historical data? I am wondering how they rule out that in the 1950s/60s they saw only much sicker patients, while today a bigger population gets diagnosed and treated. Related, there may be lead time bias: https://en.wikipedia.org/wiki/Lead_time_bias https://en.wikipedia.org/wiki/Lead_time_bias Any source with discussion of these methodological issues would be helpful.
danieltillett 11y ago
What we need to do is get the price down of cancer drug development. The fundamental problem is cancer is really many diseases so that any targeted drug will only be specific for a very small subset of cancers. This means the market for any new targeted drug is very small and so the ludicrous cost of bring as new drug to market is too great to be supported by the small number of people that will use it. The cost of these new targeted drugs is basically too high for any healthcare system to support, but the we need to make the drugs even more specific if we are going to get all the cancer types. Smaller and smaller market with every rising development costs = failure.
randcraw 11y ago
Simply eliminating Phase I is the wrong solution. Entering a Phase II study before Phase I is a great way to maim or kill people. Anti-cancer drugs are often severely toxic; even the new spate of immunocentric therapies proved highly dangerous when first administered. Several early recipients died due to clueless drug administration protocols. THAT's the reason we have Phase I. Humans usually respond differently to a drug than the animals who have gone before. That said, I think the FDA should approach cancer differently than other diseases, probably by establishing a new experimental model entirely (eliminating the Phase I/II/III system). Given that canger drugs and patients and protocols must ALWAYS be administered sensitively, circumstantially, and adaptively, the current 3 phase system seems to be serving cancer patients poorly, locking them into ineffective treatments for too long, based on too much emphasis on inflexible trial policy. Experimental protocols that are more adaptive and personalized are needed. Of course, this will be very hard technically and insanely expensive clinically. How to begin this? Like Obama, I'd love to see a 'moon shot' reinvention of the cancer business. Perhaps a project-based redesign of the system is possible, by engaging the most innovative cancer research clinicians and data analysts to explore alternative models for cancer research and drug trials. If that's what Obama has in mind, I support his wish. Now how do we make it work?
- sjg007 11y ago
  I meant in cases where the drug is already FDA approved e.g. Phase I trial has already been completed in other cancer types. There is no need to do another Phase I trial just because it is another cancer type. The restrictions on using an approved drug for a new cancer type or stage is silly. The original NCI program for treating Leukemias worked pretty well. The FDA is extremely risk adverse which is not what you want for terminal cancer treatment.

fallous 11y ago

"Cancer" isn't a single disease or problem domain, but what could be categorized as a syndrome that shares some basic commonalities. The governmental "War on Cancer" began under Nixon and was pitched as a "moonshot" type of program, which promptly ran aground on the realities of cancers. If only there were some sort of documentation for this kind of effort... perhaps they could call it "The Emperor of All Maladies" or something.

Outdoorsman 11y ago
Excellent PBS documentary you ironically refer to... http://www.pbs.org/show/story-cancer-emperor-all-maladies/ http://www.pbs.org/show/story-cancer-emperor-all-maladies/ Quite a beast to conquer, for the reason you stated...errant DNA replication, probably the single most powerful software on Earth, gone beserk... Obama's "moonshot" reference likely refers to a proposed attempt at re-centralizing the efforts of earlier research projects, to consolidate and benefit from known gains... "Moonshot" is probably simply the hyperbole choice of a speechwriter, designed to inflate the magnitude and importance of the endeavor...
- adenadel 11y ago
  The book is excellent as well http://www.amazon.com/Emperor-All-Maladies-Biography-Cancer/dp/1439170916/ http://www.amazon.com/Emperor-All-Maladies-Biography-Cancer/...
  - ggreer 11y ago
    For those interested in reading this book: Your mileage may vary. I wanted to like it, but I couldn't get over the writing. It had so many flourishes and unnecessary descriptions that I stopped reading halfway through.
nonbel 11y ago
>'"Cancer" isn't a single disease or problem domain, but what could be categorized as a syndrome that shares some basic commonalities.' Cancer is characterized by having cells with an abnormal number of chromosomes and genetic instability. It is one disease. I don't know the origins of it, but this "many disease" claim sounds like an excuse for lack of progress in targeting aneuploid cells. "In contrast to normal cells, aneuploidy--alterations in the number of chromosomes--is consistently observed in virtually all cancers." https://www.ncbi.nlm.nih.gov/pubmed/15549096 https://www.ncbi.nlm.nih.gov/pubmed/15549096

chrisamiller 11y ago

I don't agree with much that Tom Coburn says, but he's right that 'data silos' are a big problem in cancer research. To elaborate on a few points: - While enrolling 500 people with breast cancer in a study might be easy enough at one academic hospital, there are lots of rare cancer types. It's fiendishly hard to gather enough cases to do real research on these, and samples are like gold, so people are resistant to sharing. - There's lots of duplication of effort. While studies funded by the NIH are required to deposit their data, what's being deposited is raw sequence data, which requires lots of computation, disk, and skill to turn back into useful information about the mutations in cancer. - The clinical data (phenotype) that is released with studies is often incomplete or vague enough to be useless - Getting data into and out of these access-controlled repositories is, to put it mildly, a pain in the ass. We do need to protect people's privacy, but removing some of these hurdles would go a long way towards accelerating the field.

downunder 11y ago

I think we should be talking about 'uranushots' rather than moonshot because 1. the moon is close and now relatively ho-hum while uranus is in another category altogether; 2. For these things to happen a little good luck is required.

deleted 11y ago
[deleted]

aaronmck 11y ago

Well, better / more uniform access to patient records would be nice, but more money into basic research is probably the best bet (as it has always been). It makes me think of this Gregory Petsko commentary (open access): http://www.genomebiology.com/2001/3/1/comment/1001 http://www.genomebiology.com/2001/3/1/comment/1001 With the great quote: "...If a hundred years of cancer research has taught us anything, it is that if you must get cancer, you want to be a mouse, because we can cure cancer in mice."

nonbel 11y ago
"...If a hundred years of cancer research has taught us anything, it is that if you must get cancer, you want to be a mouse, because we can cure cancer in mice." Maybe it is cheaper to keep trying and there is less oversight so more BS gets through...
danieltillett 11y ago
>”...because we can cure cancer in mice.” Actually as far as I know we can’t cure mice of cancer - by cancer I mean natural cancers that mice get as they age just like human cancers. I have looked through the literature in great detail and I can’t find a single recent paper where anyone has even tried curing mice of cancer. If anyone know of one I would love to read it. The way we go about trying to cure cancer is insane. We basically take inbred mice, inject them with a cancer cell line to give them cancer, and then treat them with experimental drug X. This process is nothing like how real human cancers arise. On top of this we only test new drugs in people that have failed all other treatments and have very high tumour burdens. We then demand that the new drug have a significant effect in these patients despite us needing drugs that work in newly diagnosed patients. If we get a drug that works it is more by chance than design.
- nonbel 11y ago
  >"I have looked through the literature in great detail and I can’t find a single recent paper where anyone has even tried curing mice of cancer." It's interesting how your perspective will change after reading the literature. It is the same thing with the various mutations claimed to cause cancer. For example, in this thread someone claims mutations to BRAF cause cancer. I am nearly certain that inspecting the literature will not result in any studies where that gene in a normal cell was mutated, and then it took on the properties of a cancer cell. Maybe we will see some data on many cell generations later and in conjunction with various other treatments, but not the direct experiment of "non-cancer cell + BRAF mutation = cancer cell" while "non-cancer ell + control treatment = non-cancer cell".