ISAL 2025 | Understanding the therapeutic index of conventional chemotherapy and how it cures some patients

Yeah, I’d love to. I was very happy to see Gail Roboz just briefly echo some of those same questions where she was asking why we don’t ask often enough how we ever cure patients with chemotherapy. I think one of the reasons why we don’t ask those questions enough is because most of the cures that we’ve seen in medical oncology by treating people with drugs is from conventional chemotherapy agents that are way off patent. They’re not sexy and new and targeted, and yet they are some of the most effective agents we have. So it really begs the question, why and how do conventional agents have any sort of a therapeutic index? When we think about targeted therapies, it’s not immediately obvious that the target of conventional chemotherapy is selective to cancer cells. They largely target DNA and microtubules. These are things that normal cells have as well as cancer cells. So it’s not immediately clear what the difference is. I think a very important difference has to do with how ready the cell is to undergo apoptosis. That is, I think when you apply a DNA-damaging or microtubule-disrupting agent or some other fairly broad perturbation to a human bearing a tumor, probably all the cells in the body endure some type of perturbation and elicit some type of apoptotic signaling. However, some cells are perched close to the threshold of apoptosis and some are perched further away. It turns out, and we’ve studied this for a long time, most of the normal cells in our body that exist in vital organs are perched far away from the threshold of apoptosis. So even if they endure a certain amount of apoptotic signaling, it’s not enough for them to commit to programmed cell death and irreversibly die. However, a lot of cancer cells, including a lot of AML cells, are perched relatively close to that threshold. And we have found that that position, being able to measure that position by a method we call BH3 profiling, is sufficient in many cases to predict response to chemotherapy. So I think a very important therapeutic index that permits cure in some cases, particularly of blood cancers, that therapeutic index in many cases is based on this property of the cancer cells you’re treating being much more primed for apoptosis than the normal cells, given the therapeutic index that permits cure.

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