Abstract IA19: Targeting the BCL-2 family in breast cancer

Abstract

Abstract The steps taken to evade cell death are a recognized hallmark of cancer. Intense efforts over the last three decades have provided important insights into the molecular mechanisms that govern programmed cell death and how tumors recalibrate key survival pathways to sustain their growth. The pro-survival protein BCL-2 is overexpressed in approximately 75% of breast cancer, where it is has emerged as an important prognostic marker. Indeed, BCL-2 expression is a key component of the Oncotype DX assay. BCL-2 overexpression is even more prominent in luminal tumors (~85%), reflecting its estrogen-responsiveness. Other key pro-survival family members, MCL-1 and BCL-XL, are also commonly expressed across breast cancer subtypes. This group of pro-survival guardian proteins play a critical role in keeping pro-apoptotic effector proteins (such as BAX and BAK) in check. The effector proteins are essential for commitment to apoptosis, which occurs following mitochondrial cytochrome c release and caspase activation, resulting in cell death. BCL-2 guardian proteins also neutralize a group of sensor proteins (such as BIM). The sensor proteins are triggered by distinct cytotoxic stimuli (such as chemotherapy) to activate the effectors BAX and BAK. The sensor proteins are termed BH3 only proteins, as they lack the BCL-2 Homology (BH) domains BH1, BH2 and BH4 found in the two other subgroups. While BCL-2 is an important prognostic marker in breast cancer, its precise role as a predictive marker of tumor response has yet to be properly clarified. Nevertheless, there is increasing evidence that augmented levels of pro-survival BCL-2 proteins can prime tumors for death induced by conventional chemotherapy or endocrine therapy. This is due to the high occupation of pro-survival BCL-2 proteins by pro-apoptotic BH3 proteins, which can be activated by therapy, thereby committing tumor cells to apoptosis. Small molecule inhibitors termed BH3 mimetics that bind and neutralize BCL-2 pro-survival proteins have recently been described. These are showing considerable promise in early phase studies of lymphoid malignancies. We recently explored the feasibility of targeting luminal B tumors in combination therapy comprising endocrine therapy (tamoxifen) and a BH3 mimetic (ABT-737 or ABT-199) using patient derived xenograft (PDX) models of primary breast cancer. Tumor response and overall survival were significantly improved by combination therapy, when compared to tamoxifen alone. Moreover, synergy between BH3 mimetics and PI3K/mTOR inhibitors could be exploited by concomitant targeting of both survival pathways, a strategy that appeared both safe and effective. Since the potent and selective BCL-2 inhibitor ABT-199 was effective in these models (despite abundant BCL-XL expression), BCL-2 may be a crucial target for some luminal tumors, where we speculate it could provide a suitable companion biomarker for patient selection. This work has formed the basis for a Phase 1b study of BCL-2 inhibition with ABT-199 (venetoclax) in combination with tamoxifen in metastatic ER-positive breast cancer (ISRCTN98335443). The prospects for the development of BCL-XL and MCL-1 inhibitors will also be discussed. Citation Format: Geoffrey J. Lindeman, Delphine Merino, François Vaillant, James R. Whittle, Sheau Wen Lok, Kylie Shackleton, Jane E. Visvader. Targeting the BCL-2 family in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA19.