4 ms·

This is really early stage research being filtered through a PR team, so don't read too much into the results here yet in terms of whether all solid tumors actu

This is really early stage research being filtered through a PR team, so don't read too much into the results here yet in terms of whether all solid tumors actually have this in common and if it's actually an Achilles heel - cancer is very good at mutating and developing resistance. Here's some speculation on whats going on here. First, a useful tautology in natural selection - for a cell to be able to survive in an environment, it has to be able to survive in said environment. So the reason all solid tumors would have this is in common is because they share acidic environments (a side effect of low oxygen environments created by the tumors themselves), so they all would have adaptations to survive in these environments. Tumors are naturally hypermutative, so they have some evolutionary advantages when it comes to developing resistance. Statistically, this particular gene being unregulated might be the easiest way to develop acid resistance, so we see that most often. I would be unsurprised if after inhibiting this enzyme, we saw new approaches pop up - cancer mutates fast. Healthy cells would likely have a much harder time surviving in these environments (though most solid tumors have tons of healthy cells - they might be getting protection from the tumor cells or using some other mechanism). For those healthy cells, if their DNA is more stable or they don't replicate as quickly as cancer cells, they're going to have a hard time adapting, unless this is a general stress response mechanism that's really easy to upregulate. If it is a general response, I'd be curious about the general use cases for the enzyme and what the side effects would be of inhibiting it. Sorry it's not a straightforward response, but even with very well understood cancer genes, the narrative is never as simple as what these PR articles state, and especially for a recent discovery, its quite a claim to say that you've found a general Achilles Heel for solid tumors, an incredibly diverse class of tumors that are by their nature highly evolutionary unstable and quickly adapting, and also similar enough to normal cells that its hard to discriminate between the two with drugs.

jcims 5y ago
I don’t know if you know the answer to this but one thing that I have noticed in any personal research into cancer therapy trials is that it seems that many organizations are looking for single drug treatments, potentially to the exclusion of including other drugs in trials. Anyone that has been through chemo knows that this is not where it ends up most of time, but it really seems like companies are trying to push monotherapies as much as possible. For example, antiangiogenic drugs that help reduce the vascularization of tumors would seem to be a perfect complement to this, but if you look at the phase 1 trial there were no other drugs included in the study. I can certainly understand why it makes sense to focus on the effects of a single pharmaceutical, but in order to blend doses they’re going to have to go back to a trial most likely to see the effects of the compound treatment. This takes time that many people don’t have.
- epistasis 5y ago
  Any single agent will usually need to prove itself as somewhat efficacious on its own. Almost certainly, safety (phase 1 trial) will be tried as a single agent before trying combination therapies. However, some of our best chemotherapy regimes are combinations of many agents, such as FOLFOX and FOLFIRI in colon cancer. But to get there was a long process. There is an idea of synthetic lethality, where a single gene getting shut off by a drug has no effect, but combining (the synthesis part) with a second gene getting shutoff causes cell death. This is an extreme case of epistasis (my gene name), but the challenge of doing trials with this is that the search space is quadratic or worse, rather than linear. And number of people enrolled in clinical trials is an extremely valuable resource. Which is what leads to making sure that we start with single agent trials, to prove both safety and hopefully efficacy of these single agents. The combinations come later, because they are so complex and difficult in terms of finding something with efficacy and in terms of managing side effects and adverse events.
  - jcims 5y ago
    What you're saying makes complete sense. I just struggle at times with decisions like these because because there are millions of people sick today where the disease has broken through Avastin's ability to constrain tumor size and this might be what's needed to put it over the edge. On the other hand, anti-angiogenics are frequently not even made available in a post surgery context, particularly if perforations are a concern, so having some kind of agent that can throttle tumor growth without impacting compromised tissue would be a benefit. I guess there are no good answers until we can do whole body simulations to test drugs and all of their corner cases en masse.

jcims 5y ago

I don’t know if you know the answer to this but one thing that I have noticed in any personal research into cancer therapy trials is that it seems that many organizations are looking for single drug treatments, potentially to the exclusion of including other drugs in trials. Anyone that has been through chemo knows that this is not where it ends up most of time, but it really seems like companies are trying to push monotherapies as much as possible. For example, antiangiogenic drugs that help reduce the vascularization of tumors would seem to be a perfect complement to this, but if you look at the phase 1 trial there were no other drugs included in the study. I can certainly understand why it makes sense to focus on the effects of a single pharmaceutical, but in order to blend doses they’re going to have to go back to a trial most likely to see the effects of the compound treatment. This takes time that many people don’t have.

epistasis 5y ago
Any single agent will usually need to prove itself as somewhat efficacious on its own. Almost certainly, safety (phase 1 trial) will be tried as a single agent before trying combination therapies. However, some of our best chemotherapy regimes are combinations of many agents, such as FOLFOX and FOLFIRI in colon cancer. But to get there was a long process. There is an idea of synthetic lethality, where a single gene getting shut off by a drug has no effect, but combining (the synthesis part) with a second gene getting shutoff causes cell death. This is an extreme case of epistasis (my gene name), but the challenge of doing trials with this is that the search space is quadratic or worse, rather than linear. And number of people enrolled in clinical trials is an extremely valuable resource. Which is what leads to making sure that we start with single agent trials, to prove both safety and hopefully efficacy of these single agents. The combinations come later, because they are so complex and difficult in terms of finding something with efficacy and in terms of managing side effects and adverse events.
- jcims 5y ago
  What you're saying makes complete sense. I just struggle at times with decisions like these because because there are millions of people sick today where the disease has broken through Avastin's ability to constrain tumor size and this might be what's needed to put it over the edge. On the other hand, anti-angiogenics are frequently not even made available in a post surgery context, particularly if perforations are a concern, so having some kind of agent that can throttle tumor growth without impacting compromised tissue would be a benefit. I guess there are no good answers until we can do whole body simulations to test drugs and all of their corner cases en masse.