Preclinical Evaluation of BCL2/BCLXL Inhibition to Enhance the Efficacy of Antibody-Drug Conjugates (ADCs) for the Treatment of Distinct Breast Cancer Subtypes
Abstract
Our proposal addresses the Breast Cancer Research Program Breakthrough Award challenge to "eliminate the mortality associated with metastatic breast cancer." The mortality of metastatic breast cancer is due to the development of resistance to multiple therapies. While many different factors can contribute to therapy resistance, BCL2-family proteins that inhibit therapy-induced cell death contribute significantly to multi-drug resistance. Thus, targeting these proteins to enhance tumor cell death caused by standard-of-care drugs represents an attractive therapeutic strategy. While highly efficacious inhibitors of BCL2-family proteins have been developed and tested in clinical trials, their use in combination with chemotherapeutic drugs has been limited due to side effects of the drug combinations. To avoid the systemic effects of combining chemotherapeutic drugs with inhibitors of BCL2-family proteins, we developed drug combinations that include (1) an antibody-drug conjugate (ADC) to deliver a powerful cytotoxic payload specifically to tumor cells, avoiding systemic toxicity to healthy tissues, and (2) pulsatile delivery of an inhibitor of two BCL2-family proteins to enhance tumor cell killing and reduce side effects related to platelet depletion caused by BCL2/XL inhibition. These drug combinations offer significant promise to provide much more efficacious tumor elimination and reduce the mortality of metastatic breast cancers. In preliminary studies, we have investigated such a drug combination for the treatment of HER2+ breast cancers. One of the most recent advances in the treatment of HER2+ breast cancer is the antibody-drug conjugate T-DM1, which consists of the HER2 monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent DM1. T-DM1 has proven clinical benefits for patients with metastatic and advanced metastatic breast cancer who have progressed on prior HER2-targeted therapies. However, despite initial responsiveness to T-DM1, drug resistance ultimately occurs and leads to cancer progression. Thus, addressing the challenge of eliminating the mortality of HER2+ breast cancer represents a high priority for breast cancer investigators. We have found that treatment of two HER2+ patient derived xenograft (PDX) models with T-DM1 in combination with ABT-263, an inhibitor of BCL2/XL proteins that is currently in Phase I/II clinical trials, dramatically enhances the ability of T-DM1 to kill resistant breast tumor cells. While ABT-263 has dose limiting toxicity due to thrombocytopenia (low platelet count), we have found that a pulsed dosing schedule permits platelet recovery, eliminating chronic thrombocytopenia. The studies proposed in this application aim to further characterize T-DM1 combination treatment in additional models of advanced and/or metastatic HER2+ breast cancer in order to investigate the following issues: (1) combination therapy effectiveness across a broader range of HER2+ breast cancers, including ER+ and ERPDX models of chemotherapy and trastuzumab-resistant disease; (2) effectiveness of combination therapy in either reducing relapse after T-DM1 therapy, or in metastatic tumors; and (3) the effectiveness of combined BCL2 and BCL-XL inhibition compared to selective inhibition of either anti-apoptotic protein. In addition, the studies proposed in this application aim to determine whether ABT-263 could enhance the effectiveness of IMMU-132, a novel ADC for the treatment of patients with triple-negative breast cancer (TNBC). This ADC is currently in Phase I/II clinical trials for TNBC and other solid tumors that express the IMMU-132 target TROP2. IMMU-132 carries an active metabolite of irinotecan, SN-38, which has proven efficacy in TNBCs. Importantly, SN-38 has been shown to be less toxic than other ADC cargos, thus permitting greater delivery of the drug over repeated cycles of therapy and thereby improving therapeutic index. The studies proposed in this applicatio
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610340
Entities
People
- Joan Brugge
Organizations
- Harvard University
- United States Army