Functional Drug Screening of Small Molecule Inhibitors of Epigenetic Modifiers in Refractory AML Patients

SIMPLE SUMMARY: Acute myeloid leukemia is a cancer originating in the bone marrow and peripheral blood. Genetic mutations observed with the disease are difficult to target therapeutically and patients often have different treatment responses to the standard of care. By finding epigenetic compounds that work in a variety of patients, we could discover better therapies to treat the disease apart from the current standard of care. Here we present an unbiased drug screen of a variety of epigenetic compounds, with some showing effective responses in all or most patient samples. ABSTRACT: The use of inhibitors of epigenetic modifiers in the treatment of acute myeloid leukemia (AML) has become increasingly appealing due to the highly epigenetic nature of the disease. We evaluated a library of 164 epigenetic compounds in a cohort of 9 heterogeneous AML patients using an ex vivo drug screen. AML blasts were isolated from bone marrow biopsies according to established protocols and treatment response to the epigenetic library was evaluated. We find that 11 histone deacetylase (HDAC) inhibitors, which act upon mechanisms of cell cycle arrest and apoptotic pathways through inhibition of zinc-dependent classes of HDACs, showed efficacy in all patient-derived samples. Other compounds, including bromodomain and extraterminal domain (BET) protein inhibitors, showed efficacy in most samples. Specifically, HDAC inhibitors are already clinically available and can be repurposed for use in AML. Results in this cohort of AML patient-derived samples reveal several epigenetic compounds with high anti-blast activity in all samples, despite the molecular diversity of the disease. These results further enforce the notion that AML is a predominantly epigenetic disease and that similar epigenetic mechanisms may underlie disease development and progression in all patients, despite differences in genetic mutations.