Abstract P2-09-01: Targeting BCL-2 with the BH3 mimetic ABT-199 in ER-positive breast cancer
Authors: Lindeman GJ , Vaillant F , Merino D , Lee L , Breslin K , Pal B , Ritchie ME , Smyth GK , Christie M , Phillipson LJ , Burns CJ , Mann GB , Visvader JE 
Published: August 2014

Background: Impairment of apoptosis is a hallmark of cancer and can result in resistance to therapy. Over-expression of the pro-survival protein BCL-2 is common in breast cancer, with elevated levels found in approximately 85% of luminal tumors. Although BCL-2 has been shown to be an important prognostic marker, its role as a therapeutic target has yet to be fully explored. Small molecule inhibitors termed ‘BH3 mimetics’ that mimic the action of pro-apoptotic BH3-only proteins have recently been developed. These bind and neutralize BCL-2 pro-survival proteins. We have previously shown that the BH3 mimetic ABT-737 (which neutralizes BCL-2, BCL-XL and BCL-W) synergizes with docetaxel in BCL-2-positive patient-derived xenograft (PDX) models. Recently, a potent BCL-2-specific inhibitor, ABT-199, has been developed that is showing considerable promise in early phase studies of lymphoid malignancies. Since BCL-2 expression is prominent in the luminal B tumors, we sought to determine whether it might be feasible to target luminal B tumors with combination therapy comprising endocrine therapy (tamoxifen) and a BH3 mimetic (ABT-737 or ABT-199), using novel PDX models of luminal B breast cancer.

Methods and Results: A panel of 36 primary breast tumor xenografts (including 15 luminal tumors) was generated in immunocompromised (NOG) mice. Three BCL-2-positive luminal B models (23T, 315T, 50T), as determined by Ki-67 immunostaining and gene expression profiling, and a control BCL-2-positive, ER-negative model (838T) were selected for further study. Cohorts of mice bearing tumor xenografts were treated with either ABT-737 (50 mg/kg i.p. d1-10), tamoxifen or both agents in q21d cycles. Tumor response and overall survival were significantly improved by combination therapy in all three ER-positive xenograft models, when compared to tamoxifen alone (p&lt;0.005). Despite abundant BCL-XL expression in tumors, similar efficacy was observed with the selective BCL-2 inhibitor ABT-199 (50 mg/kg o.g. d1-5 and 8-12 q21d) and tamoxifen (p&lt;0.005), revealing that BCL-2 is a crucial target. Unexpectedly, both BH3 mimetics were found to counteract the side effect of tamoxifen-induced endometrial hyperplasia. In addition, we observed that BH3 mimetics synergized with dual PI3K/mTOR inhibitors in the induction of apoptosis. In the 315T model, where AKT was found to be activated, triple therapy with ABT-737, a PI3K/mTOR inhibitor (PKI-587) and tamoxifen further augmented tumor response in vivo, when compared to ABT-737 and tamoxifen (p&lt;0.004).

Discussion: Patient derived xenograft models of luminal B breast cancer have been derived that recapitulate the phenotype of the primary tumor. Here we have demonstrated that concomitant targeting of BCL-2 confers marked benefit above tamoxifen alone. Moreover, synergy between BH3 mimetics and PI3K/mTOR inhibitors could be exploited by targeting of both survival pathways, a strategy that appeared both safe and effective. Collectively, our findings provide a rationale for clinical evaluation of BH3 mimetics in early phase studies in breast cancer. Here, BCL-2 protein or mRNA expression (as determined by immunohistochemistry or RT-PCR, respectively) could provide a suitable companion biomarker for patient selection.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-01.