Project 3: BET bromodomain inhibitor combinations in breast cancer

Dana-Farber Cancer Inst, Boston MA

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY Immune checkpoint blockade (ICB) in combination with chemotherapy is an approved treatment for a subset of patients with triple-negative breast cancer (TNBC), but the limited clinical efficacy in the metastatic setting suggests that the immunosuppressive microenvironment cannot be overcome by ICB alone. Similarly, CDK4/6 inhibitors (CDK4/6i) are highly effective for the treatment of estrogen receptor positive (ER+) breast cancer but inherent and acquired resistance inevitably occurs. To improve outcomes, this project will test the hypothesis that combining BET bromodomain inhibitors (BBDI), an emerging class of targeted breast cancer therapy, with ICB plus paclitaxel and with CDK4/6i will be an effective therapeutic strategy for metastatic TNBC and CDK4/6i- resistant ER+ breast cancer, respectively. The rationale for this work is based on our published and preliminary data in preclinical models demonstrating that (1) BBDI synergize with paclitaxel and CDK4/6i and overcome resistance to each single agent, and (2) anti-PD-1, paclitaxel, BBDI triplet combination is the most effective to prolong survival and induce T and B cell infiltration and cancer cell senescence. Two specific aims are proposed. In Aim 1 the effects of BBDI in combination with paclitaxel and anti-PD-1 will be evaluated in mouse models of metastatic and paclitaxel-resistant TNBC. Changes in cellular composition and molecular profiles will be analyzed. Requirement for specific immune cell populations (e.g., B cells) and senescence will be assessed by depletion studies. A Phase 1 dose-escalation trial combining the ZEN-3694 BBDI, pembrolizumab, and nab- paclitaxel will be performed, in which tumor biopsies will be analyzed for changes in the immune microenvironment, senescence, and copy number and expression of CD274, encoding PD-L1. In Aim 2 combinations of BBDI and CDK4/6i (e.g., abemaciclib) will be tested in human ER+ breast cancer models with different mechanisms of resistance to CDK4/6i as well as in ER+ rat mammary tumor models. A phase 2 trial will be planned to evaluate the efficacy and safety of ZEN-3694 plus abemaciclib and fulvestrant in metastatic ER+/HER2- breast cancer with acquired endocrine and CDK4/6i resistance. The successful completion of this project will improve our understanding of the immune effects of these targeted therapies and may identify biomarkers to aid the selection of patients most likely to benefit from these combinatorial strategies.