3 ms·

This is not as big a problem as: 1. Enrolling enough people in a trial to prove you can cure with a combination therapy 2. Evolved resistance with an entirely

This is not as big a problem as: 1. Enrolling enough people in a trial to prove you can cure with a combination therapy 2. Evolved resistance with an entirely new set of mutations

danieltillett 11y ago
Well these two problems are technical problems that can only occur if the key economic problem can be overcome. You can only have issues with enrolling people in a trial if the trial is at least attempted. The current thinking is that cancers are not evolving for resistance during treatment, but that there are a sub-population of cells present in the tumour mass that are being selected for by treatment (i.e. we kill 99% of the tumour that is sensitive and the 1% that is resistant grows back). We know how to solve this problem from HIV. HIV evolves resistance to drugs faster than any cancer yet we can treat patients for years by using HAART (i.e. give lots of drugs at once that target different key components). We need to do this with cancer, but this will require developing new drugs that are less lethal since you can't just give a patient a dozen standard anti-cancer drugs and expect them to live.
- astazangasta 11y ago
  >The current thinking is that cancers are not evolving for resistance during treatment, but that there are a sub-population of cells present in the tumour mass that are being selected for by treatment (i.e. we kill 99% of the tumour that is sensitive and the 1% that is resistant grows back). No, the cancer evolves resistance during treatment. Evolution is change in allele frequency in a population over time, not the emergence of new mutation. It does not matter whether the mutation was a rare, preexisting mutation or it occurred after treatment; both likely happen. The "evolution" part is the outgrowth as a result of a fitness differential produced by the new environment (therapy). >We know how to solve this problem from HIV. HIV evolves resistance to drugs faster than any cancer yet we can treat patients for years by using HAART (i.e. give lots of drugs at once that target different key components). We need to do this with cancer, but this will require developing new drugs that are less lethal since you can't just give a patient a dozen standard anti-cancer drugs and expect them to live. We will never be able to do this with cancer. HIV has only nine proteins in its genome. This means any resistance mutation it develops must be on-target and will tend to operate through specific bottleneck points. This is not true with cancer - there is on-target resistance, of course, but this is easily overcome through better drug design. We can develop drugs that get around EGFR T790M, but in a cancer there are a dozen different new mutations in other genes that can emerge to produce resistance. Drugging all of these targets in advance is impossible - we can barely drug one gene with patients tolerating it. We'll lose this game of whack-a-mole. This is a losing game in general. The tumor has too much space to adapt - it's not limited to a tiny genomic space like HIV, it has the whole human genome to work with. This is why I think successful strategies are going to result from not inhibiting particular genes but treating the tumor as a tissue and modulating the host/tumor interactions. Immunotherapy acts on this axis, and it's already looking more promising in this regard (responders don't tend to become resistant).
  - danieltillett 11y ago
    I think we are in agreement, but you did say "2. Evolved resistance with an entirely new set of mutations”. I was pointing out that evolution is not coming about from the selection of new mutations, but the selection of pre-existing mutations present with the tumour before treatment. >Drugging all of these targets in advance is impossible - we can barely drug one gene with patients tolerating it. We'll lose this game of whack-a-mole. It is not impossible, just difficult. It will certainly be impossible if we keep trying to develop new treatments the way we have for the last 50 years. We need to change the entire way we screen and test new cancer treatments if we are going to be able to use the HAART approach in human cancer. I agree with you that immunotherapy is looking the most promising approach right now, but done right chemotherapy has a lot of potential too. I would not rule one or the other out.

This is not as big a problem as: 1. Enrolling enough people in a trial to prove you can cure with a combination therapy 2. Evolved resistance with an entirely new set of mutations

danieltillett 11y ago

Well these two problems are technical problems that can only occur if the key economic problem can be overcome. You can only have issues with enrolling people in a trial if the trial is at least attempted. The current thinking is that cancers are not evolving for resistance during treatment, but that there are a sub-population of cells present in the tumour mass that are being selected for by treatment (i.e. we kill 99% of the tumour that is sensitive and the 1% that is resistant grows back). We know how to solve this problem from HIV. HIV evolves resistance to drugs faster than any cancer yet we can treat patients for years by using HAART (i.e. give lots of drugs at once that target different key components). We need to do this with cancer, but this will require developing new drugs that are less lethal since you can't just give a patient a dozen standard anti-cancer drugs and expect them to live.

astazangasta 11y ago
>The current thinking is that cancers are not evolving for resistance during treatment, but that there are a sub-population of cells present in the tumour mass that are being selected for by treatment (i.e. we kill 99% of the tumour that is sensitive and the 1% that is resistant grows back). No, the cancer evolves resistance during treatment. Evolution is change in allele frequency in a population over time, not the emergence of new mutation. It does not matter whether the mutation was a rare, preexisting mutation or it occurred after treatment; both likely happen. The "evolution" part is the outgrowth as a result of a fitness differential produced by the new environment (therapy). >We know how to solve this problem from HIV. HIV evolves resistance to drugs faster than any cancer yet we can treat patients for years by using HAART (i.e. give lots of drugs at once that target different key components). We need to do this with cancer, but this will require developing new drugs that are less lethal since you can't just give a patient a dozen standard anti-cancer drugs and expect them to live. We will never be able to do this with cancer. HIV has only nine proteins in its genome. This means any resistance mutation it develops must be on-target and will tend to operate through specific bottleneck points. This is not true with cancer - there is on-target resistance, of course, but this is easily overcome through better drug design. We can develop drugs that get around EGFR T790M, but in a cancer there are a dozen different new mutations in other genes that can emerge to produce resistance. Drugging all of these targets in advance is impossible - we can barely drug one gene with patients tolerating it. We'll lose this game of whack-a-mole. This is a losing game in general. The tumor has too much space to adapt - it's not limited to a tiny genomic space like HIV, it has the whole human genome to work with. This is why I think successful strategies are going to result from not inhibiting particular genes but treating the tumor as a tissue and modulating the host/tumor interactions. Immunotherapy acts on this axis, and it's already looking more promising in this regard (responders don't tend to become resistant).
- danieltillett 11y ago
  I think we are in agreement, but you did say "2. Evolved resistance with an entirely new set of mutations”. I was pointing out that evolution is not coming about from the selection of new mutations, but the selection of pre-existing mutations present with the tumour before treatment. >Drugging all of these targets in advance is impossible - we can barely drug one gene with patients tolerating it. We'll lose this game of whack-a-mole. It is not impossible, just difficult. It will certainly be impossible if we keep trying to develop new treatments the way we have for the last 50 years. We need to change the entire way we screen and test new cancer treatments if we are going to be able to use the HAART approach in human cancer. I agree with you that immunotherapy is looking the most promising approach right now, but done right chemotherapy has a lot of potential too. I would not rule one or the other out.