P-094: ABT-199 and epigenetic modifiers: promising novel combinations for the treatment of Multiple Myeloma

Abstract

Multiple Myeloma (MM) is a malignancy of the antibody-producing plasma cells. Despite improvements to treatment throughout the years, it remains an incurable and fatal disease [1]. Therefore, novel innovative therapies are needed for relapsed/refractory MM. The anti-apoptotic BCL-2 family of proteins (BCL-2, BCL-XL and MCL-1) are critical regulators of the intrinsic apoptotic pathway and determine the survival of human MM cells [2,3]. The anti-apoptotic BCL-2 proteins represent attractive therapeutic targets in MM. Recently, ABT-199, a selective BCL-2 inhibitor, was FDA approved for the treatment of CLL and AML. The aim of the study is to develop a biomarker to identify MM patients that are reliant on BCL-2 and could be treated with ABT-199. To assess anti-apoptotic dependence, we used BH3 profiling, a functional assay that interrogates BCL-2 protein interactions using synthetic BH3 peptides to measure the loss of mitochondrial membrane potential. We screened a panel of BH3 mimetics in MM cells and patient bone marrow samples; ABT-199 (selective BCL-2 inhibitor), ABT-263 (BCL-2, BCL-xL and BCL-W inhibitor), WEHI-539 (BCL-XL inhibitor) and AMG-176 (selective MCL-1 inhibitor). The BH3 profile data and BH3 mimetics sensitivity data revealed that there is a diverse anti-apoptotic dependence in MM cell lines and primary patient samples. In addition, we aim to identify novel combination treatments that will induce BCL-2 dependence in MM cells, enhancing sensitivity to ABT-199 treatment. We performed a small molecule screen to identify epigenetic modifiers that could induce BCL-2 dependence in two MM cell lines. The screen included the following classes of epigenetic drugs: histone deacetylase inhibitors, histone methyltransferase inhibitors, DNA methyltransferase inhibitors and BET inhibitors. Interestingly, two classes of the epigenetic drugs, were synergistic with ABT-199 in three MM cell lines, (CI <0.8). Furthermore, we confirmed enhanced cell death by Annexin V/PI staining following both ABT-199 and the two classes of epigenetic drugs in two patient MM samples ex-vivo. Future work will focus on determining the mechanism of enhanced cell death induced by the epigenetic drugs to improve the response to ABT-199 treatment.