This Proposal describes the existing and proposed future activities of a consortium of three research groups in the Boston, MA area whose research has been focused over the past two decades on the pathogenesis of human breast cancer. All three current Project Leaders and the Pathology Core have worked together in a prior P01 led by Dr. Robert Weinberg (Whitehead Institute for Biomedical Research, Cambridge, MA) for 21 years. As such, the proposed Team has a long history of productive collaborative projects and well-established mechanisms in place to facilitate interactions. The primary focus of the three research groups is to improve our understanding of mechanisms of resistance to currently used therapies and to identify and characterize new therapeutic targets and combination therapies with the goal of clinical translation of the Program's preclinical findings; indeed, some of our findings have already inspired the design of FDA-approved therapeutics with several clinical trials in progress. The interactions between the Leaders and trainees of the component Groups is driven by convening monthly research meetings throughout the academic year and a single research retreat in Western Massachusetts, during which trainees in the participating laboratories meet and present the details of their respective research findings. The productivity of this consortium depends on the complementary research interests and experimental approaches of the component Groups. The participating Groups address therapeutic resistance and novel vulnerabilities in breast cancer from various perspectives, beginning with the defining molecular mechanisms underlying heterogeneity in cellular responses to growth regulatory signals and dissecting epigenetic and transcriptomic heterogeneity in therapeutic resistance and in driving the outgrowth of distant metastases. The respective research emphases of the participating Project Groups are highly complementary and integrated. This complementarity is manifested through repeated cross-fertilization at the conceptual level, the sharing of reagents generated by one Project with others, complementary technologies, and successful joint publications.
- Overall This proposal requests the funding of a consortium of three closely interacting, Boston-area cancer research groups whose joint focus is on new therapeutic vulnerabilities in breast cancer identified based on unbiased screens and by dissecting mechanisms of resistance to current therapies. Heterogeneity for phenotypic features such as proliferation and therapeutic sensitivity is a major challenge for cancer treatment. This consortium applies the latest available technologies and computational tools to understand drivers of epigenetic and transcriptomic heterogeneity in human breast cancer in order to reveal novel and effective means of treating these tumors.
