Meet The Professors: Acute Myeloid Leukemia Edition, 2017 (Video Program) - Video 1Potential synergy between targeted therapy and chemotherapy
3:00 minutes.
TRANSCRIPTION:
DR LOVE: So maybe you comment, also, on this slide in terms of the issue of single-agent targeted therapy. DR STONE: Because AML is a complicated disease, and if you take FLT3 inhibitor therapy, for example, which I’m kind of familiar with, it’s really a stupid idea if you think about it. FLT3 is a late hit in leukemogenesis. It’s a progression mutation, so at best, theoretically, if you use it as a single agent, it’s not going to get rid of the bad clone. It’s just going to get rid of the most malignant part of the clone. And still, the patient will have some abnormalities. Plus, as we all know, cancer’s sneaky. We inhibit one clone. Another one pops up. It’s very much like “Whack-a-Mole.” And we can’t forget about chemotherapy. It works really well. So it’s often important to explore synergy between molecularly targeted therapy and, I guess, classical chemotherapy. DR LOVE: I notice you have the word “founder” mutation. We were talking about lung cancer before. The issues of tumor mutations come in. What’s the difference between a founder mutation and a driver mutation? DR STONE: A driver mutation means that it’s something important in the leukemic clone cell. FLT3 can be a driver mutation, because it’s doing something pathophysiologically. But a founder mutation is present at the onset of the leukemia and is present throughout. So if you had a choice between targeting a founder and just a late hit, you’d target the founder. And maybe some patients with IDH mutations, it’s part of the founder clone. That’s why in some patients who get an IDH inhibitor, they may have incredibly deep responses. It’s the reason why, in Philadelphia-positive ALL, in my opinion, chemotherapy, while it might be important, is of less importance, because the Philadelphia lesion, the BCR-ABL, is the founder mutation of Philadelphia-positive ALL. And using that, plus maybe some steroids, causes unbelievably fantastic and prolonged responses. So the founder is the one that’s there at the beginning, there at the end. And if you had a choice what to target, I would target that one. DR LOVE: So, for example, I’ve never heard the term used, “founder mutation.” And maybe I just didn’t hear it in, for example, tumor mutations in lung cancer; EGFR tumor mutations. Would you consider that a founder mutation? DR STONE: Probably not. It’s probably a late hit in lung cancer, but it’s still a very important one to target, because it’s — DR LOVE: A late hit. I mean, they have it at diagnosis. DR STONE: Right, but do they have it when the first cell became abnormal? DR LOVE: Hmm. Wow! DR STONE: So, I mean, if you’re talking about the biology of these cancers, they start out with 1 mutation. They get additional mutations. Does EGFR inhibition as a single agent cure anybody with lung cancer? No. But in melanoma, BRAF inhibition doesn’t cure anybody. It’s great responses. What about adding BRAF inhibition plus immunotherapy to deal with the first cell that becomes abnormal, the basic cell? And that’s when we have to think about using immunological targeting is a whole other story, but may be able to — in many cases doesn’t cure, whether it’s hitting that cell with a founder mutation or a driver mutation. |