Abstract

Selectively targeting the apoptotic pathway in human cancers has recently become a clinical reality with the FDA approval of the BCL-2 inhibitor, venetoclax, in chronic lymphocytic leukemia (CLL). How can we determine what cancers are best targeted with this type of therapy? This talk will review how BH3 profiling, a functional assay of mitochondrial dependence on anti-apoptotic proteins, identified the BCL-2 dependence of CLL. Other cancers will be discussed, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma and blastic plasmacytoid dendritic cell neoplasm (BPDCN) where BCL-2 inhibition shows promise. The talk will also outline how to identify drugs that enhance BCL-2 dependence as a strategy for rationally choosing combinations with drugs like venetoclax. While there is considerable attention paid to genomic means for matching cancers and individual patients to the right drugs, it is important to recognize the many examples, as here, of cancers that are sensitive to a targeted therapy without any indicative genetic lesion. In these cases, a functional precision medicine strategy is required.