Abstract TS3-1: Beyond B cells: Targeting BCL-2 pro-survival proteins in breast cancer
Authors: Lindeman G 
Published: May 2019

Abstract
Resisting cell death is a hallmark of cancer. B-cell lymphoma 2 (BCL-2) is the prototypic member of a 'pro-survival' family that protects against cell death (apoptosis). Considerable progress has been made in deciphering its mechanism of action since it was first identified as the gene involved in the t(14;18) chromosomal translocation in follicular lymphoma about 30 years ago. BCL-2 and other pro-survival family members MCL-1 and BCL-XL have been shown to play a central role in the intrinsic apoptotic pathway: They keep the pro-apoptotic 'effector' proteins BAK and BAX in check and also neutralize a group of 'sensor' proteins that can be activated by stress signals (including cytotoxic and targeted therapies). These sensor proteins dock onto a surface hydrophobic groove on BCL-2 through their BH3 domain. BCL-2 proteins therefore play a vital role as guardians against apoptosis by inhibiting sensor and effector protein activity.
Potent and specific 'BH3 mimetics' have recently been developed that mimic the BH3 domain of the sensor proteins. BH3 mimetics bind to and neutralize BCL-2 (and/or its pro-survival relatives) to help trigger apoptosis. Venetoclax (ABT-199/GDC-0199) is a potent and selective BCL-2 inhibitor. Its utility in targeting BCL-2 in hematological malignancies has recently become apparent, with remarkable clinical responses observed in heavily pre-treated patients with treatment refractory chronic lymphocytic leukemia, resulting in the FDA granting fast-track approval. Combination therapy with venetoclax is also showing activity in other hematological malignancies.
BCL-2 is overexpressed in approximately 80% of ER-positive (ER+) primary breast cancer, while MCL-1 overexpression is a feature of TNBC. Our group has explored the role of the BCL-2 inhibitor venetoclax and MCL-1 inhibitor S63845 in pre-clinical models of breast cancer. Using patient-derived xenograft (PDX) models of ER+ breast cancer, venetoclax was found to synergize with tamoxifen to improve tumor response by increasing apoptosis. Similarly, the MCL-1 inhibitor S63845 augmented tumor response to docetaxel in PDX models of TNBC.
These findings have led to a phase 1b dose escalation and expansion study, 'mBEP', combining venetoclax with tamoxifen in ER+ and BCL-2+ metastatic breast cancer. Findings from the dose escalation component have revealed that the combination is safe and well-tolerated and identified the recommended phase 2 dose. In the dose expansion phase, notable clinical activity has been observed. Since venetoclax therapy can be associated with 'on-target' lymphopenia, its effect on peripheral blood immune subsets was also explored.
A role for combining venetoclax with 'modern day' endocrine therapies is not known. This question may in part be informed by a randomised phase II study of fulvestrant with or without venetoclax in women with ER+ metastatic breast cancer that has progressed on a CKD4/6 inhibitor (VERONICA, WO40181), recently commenced. In addition, preliminary pre-clinical modeling suggests that combining venetoclax with fulvestrant and a CDK4/6 inhibitor can augment tumor response. Since CDK4/6 inhibitors have recently been shown to modulate immune responses, establishing the immune effects of combination therapy could also be important.
Citation Format: Lindeman G. Beyond B cells: Targeting BCL-2 pro-survival proteins in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr TS3-1.