Precision Antibody-Based Synergistic Drug Combinations for Refractory Triple-Negative Breast Cancer
Abstract
Background and Overview: Metastatic triple-negative breast cancer (mTNBC) is characterized by a limited response to standard chemotherapy and short survival, and therefore represents a major unmet clinical need. Developing conceptually new therapeutic approaches and combinations will be essential to providing patients with more effective and less toxic therapies that impact survival. In doing so, our goal is to eliminate the mortality associated with mTNBC. Our group recently led the clinical development of a highly promising new therapy for TNBC called sacituzumab govitecan (SG). SG belongs to a novel class of precision therapeutics called antibody-drug conjugates. These agents involve an antibody that specifically binds to the tumor but not normal cells, coupled to a highly potent chemotherapy that is released at the tumor upon antibody binding. Consequently, as much as 100 times more chemotherapy can be delivered specifically to the tumor with SG compared to standard chemotherapy, while sparing normal tissues. A key clinical trial of SG led by the Partnering Principal Investigator (PI) for patients with mTNBC dramatically improved patient outcomes and resulted in FDA breakthrough status for this drug. Herein, we propose to capitalize on this treatment innovation by identifying select targeted drugs for combination with SG that i) will uniquely complement/enhance its efficacy and ii) can be rapidly moved into clinical trials for TNBC patients. Research Hypotheses and Methods: To achieve this goal, we initiated a multidisciplinary collaboration, involving basic science, computational biology, and clinical and translational research, all aimed at defining the select few targets that can be combined with SG for maximum anti-tumor effect. We are uniquely positioned to carry out these studies because of our deep scientific expertise, our leadership role in the clinical development of SG, our access to tumor specimens from patients treated with SG, and our productive collaboration with the SG manufacturer to obtain supplies of this precision drug for our studies. We started with a broad, laboratory-based approach called a genome-wide screen in TNBC cells treated with SG that can identify every gene whose loss increases (or decreases) cell sensitivity to SG. Among the top genes whose loss increased sensitivity was PARP1, a DNA repair factor that can be targeted with FDA-approved drugs called PARP inhibitors (PARPi). While these findings suggest the hypothesis that combining SG with PARPi would be effective against mTNBC, concerns have been raised about potential for side effects from the combination (low blood counts). However, we hypothesize that a staggered dosing schedule (SG followed days later by PARPi) may overcome this side effect. Furthermore, we identified several other cancer-associated pathways that can be blocked with drugs currently in clinical trials to enhance the efficacy of SG. We hypothesize that with additional research, a subset of these drugs could be moved into clinical trials with SG to overcome SG resistance, and increase response rates and survival. Our methodology employs three general approaches that are highly integrated, with data from each informing the others. First is a laboratory-based component that tests the mechanisms and effectiveness of specific drug combinations with SG, asking in part whether the combinations will work in multiple different TNBC models. This is a critical test since TNBCs from different patients vary substantially in their behavior. Second is an animal-based component, in which we will test how effective the most promising combinations with SG are against TNBC tumors, how well-tolerated these combinations are, and whether staggered dosing schedules might preserve efficacy while minimizing side effects. Third is analysis of specimens from SG-treated patients, testing predicted biomarkers of response and resistance to SG, and using molecular analysis to discover new b
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110057
Entities
People
- Leif W Ellisen
Organizations
- Massachusetts General Hospital
- United States Army