Identifying human cancers to target with BCL-2 inhibition

Anthony Letai, MD, PhD of Dana-Farber Cancer Institute, Boston, MA gives an overview of his talk on identifying human cancers to target with BCL-2 inhibition at the 2016 National Cancer Research Institute (NCRI) Conference in Liverpool, UK. Dr Letai explains that in the absence of genetic alterations to direct the use of these inhibitors, they rely on a functional approach. The BCL-2 and MCL-1 inhibitors operate at the mitochondria and therefore, they have been using functional approaches for studying cancer cell mitochondria in order to predict who’s tumors will respond; this process is called BH3 profiling. He then discusses single agent sensitivity of tumors. Chronic lymphocytic leukemia (CLL) for example, looked like it should be homogeneously sensitive to BLC-2 inhibitors based on their assays; indeed, clinical trials show 80% response rates to single agent venetoclax. In acute myeloid leukemia (AML) or multiple myeloma (MM), there are subsets that are BLC-2 dependent but it is heterogenous, i.e. some subsets of tumors are sensitive to single agent BCL-2 inhibition whereas others aren’t. Dr Letai also points out that it is possible to perturb cells to become more BCL-2 dependent, as in the case of CLL and ibrutinib.

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