ISAL 2025 | Using functional precision medicine to guide treatment in AML

So I think functional precision medicine fills a void for those AML patients for whom it’s not possible to identify a genetic abnormality that connects to a drug. This is the case in all too many cancers. In the case of AML, a good example is venetoclax, where there are no mutations in BCL2 or related proteins in venetoclax that would in any way serve to indicate that venetoclax would be an effective treatment for AML. Work that I did alongside Marina Konapleva was purely functional, which is to say we just studied living patient AML cells and asked questions upon those living cells as to whether the mitochondria or the cells themselves were dependent on BCL2, which is the target of venetoclax. Having demonstrated that functionally, we were then able to propagate that into a clinical trial of venetoclax in AML that many years later and many clinical trials later performed very ably by others led to FDA approval and widespread regulatory approval. So the point I try to make, this is precision medicine. It’s doing the job of precision medicine, which is specifically finding out what drugs work for which patients. But it’s precision medicine that depends on function rather than genomics. So we call it functional precision medicine. This can be done, and the point I’d like to make is that venetoclax is a great example of how it has been done. But this same sort of approach can be used very broadly, both for the discovery of new agents, but also for stratifying patients for response to existing drugs, whether it be FLT3 inhibition or something else that’s novel, where we often struggle with finding biomarkers that perform really well. FLT3 ITD, for example, performs pretty well for FLT3 mutant patients, but its actual positive predictive value for response to FLT3 inhibitors isn’t great. We need to do better. The lessons that we’ve learned over the last decade or so have informed us that indeed when we see a signal in our assays, in our ex vivo assays, with a drug on a patient sample, it’s actually a pretty good predictor of whether there will be a clinical response. We’ve all done this so far retrospectively. So right now, in conjunction with Jacqueline Garcia and Emma Minahan in my lab, we’ve constructed a Phase II study that’s basically what you would call an umbrella study, where we’re going to assign patients to multiple different venetoclax doublet arms in the relapse setting based on the results of our functional precision medicine assay. Once we meet regulatory approval with our assay, we will be able to start enrolling for that trial.

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