Dana Farber/Harvard Cancer Center Specialized Program of Research Excellence in Breast Cancer

Dana-Farber Cancer Inst, Boston MA

Investigators

Linked publications, trials & patents

Abstract

The Dana-Farber/Harvard Cancer Center (DF/HCC) SPORE in Breast Cancer seeks to improve the understanding and treatment of breast cancer (BC) using a highly translational approach encompassing four projects, three cores, a Developmental Research Program (DRP) and a Career Enhancement Program (CEP). Each project brings together laboratory scientists and clinicians to address a fundamental challenge that results in premature mortality or substantial morbidity. Project 1 will study mechanisms of resistance to antibody drug conjugates (ADCs). Strategies will be developed to overcome resistance in triple-negative breast cancer (TNBC) through mechanism-based combinations, including those targeting PARP1 and the proteasome. Preclinical modeling of concomitant and sequential sequencing of ADCs with targeted agents will be translated to clinical trial. Project 2 will focus on breast cancer brain metastases (BCBM) across BC subtypes and will leverage our unique collection of xenografts derived from resected human BCBM, novel genetically engineered mouse models, and our experience conducting brain metastasis-specific trials. Clinical work will define the activity of ADCs in patients with BCBM. The project will exploit PTEN loss as a critical event enabling seeding of BC cells to the brain that can be targeted by PI3K inhibition. Project 3 will build on prior preclinical work demonstrating that BET bromodomain (BBD) inhibition is synergistic with chemo-immunotherapy in TNBC, promoting enhanced immunomodulation and efficacy. A clinical trial combining BBD inhibition, nab-paclitaxel and pembrolizumab will be conducted in patients with TNBC. The project will also explore BBD inhibition as a strategy to reverse CDK4/6 inhibitor resistance in ER+ BC. Project 4 will address BRCA-associated BC, and the short PFS achieved by PARP inhibitors (PARPis) that has not been improved by addition of anti-PD-(L)1, by targeting immuno-suppressive macrophages in the TME with CSF-1R blockade. Effects of PARPis on the TME in preclinical models will be validated in biopsies procured from patients treated on trials in the metastatic and neoadjuvant settings. Combined anti-CSF-1R and PARP inhibition will be studied in a Phase 1 trial and will be assessed preclinically as a strategy to reverse acquired PARPi resistance. The Administrative Core is the epicenter of scientific, fiscal, and administrative oversight. It will lead efforts in planning and communication, ensure that existing DF/HCC structures support SPORE research efforts, and will house the Patient Advocacy Committee. The Biospecimen and Pathology Core will provide pathology services for the projects, perform cutting edge assays with advanced technologies, house the Immuno-Oncology Sub Core and will maintain tissue and blood repositories. The Biostatistics and Computational Biology Core will provide expertise in biostatistics and management of genomic data. The DRP and CEP will identify novel approaches to translational questions in breast cancer and support early career investigators. With our projects, cores and research environment, the DF/HCC SPORE in Breast Cancer is poised to make substantial translational contributions.