PARP Inhibition to Treat Triple-Negative Breast Cancer Brain Metastases

DESCRIPTION (provided by applicant): Carey K. Anders, MD, an Assistant Professor of Medicine, Division of Hematology-Oncology at the University of North Carolina (UNC), is a medical oncologist with a solid training and background in clinical-translational research methodology and a proven commitment to applying these methods to the study of breast cancer, particularly brain metastases. The candidate's long-term career goal is to become an independently-funded physician-scientist with a diverse portfolio including clinical trial design, preclinical modeling, and pharmacologic studies related to breast cancer brain metastases. In particular, the candidate will design and execute clinical trials testing novel agents to treat patients with breast cancer brain metastases, in particular aggressive triple-negative disease. In parallel, she will conduct pharmacologic disposition and efficacy studies in a preclinical intracranial triple-negative breast cancer model, results which will be seamlessly translated into future clinical trials. The candidate's short-term career goals fostered by this career development award are 1) to enhance her skills in clinical trial design, implementation and execution, 2) to expand her clinical trials skills to multi-center trial coordination, 3) to gain proficiency in clinical trial data analysis and interpretation, 4) to refine her ability to conduct preclinical pharmacologic disposition and efficacy studies, 5) to attain skills in analytic pharmacology technique and interpretation, and 6) to foster the development of professional skills and collaborations to lead a multidisciplinary research team. The proposed research plan, career development activities, mentoring team, and institutional environment are well-suited to assure the applicant achieves her goals. The research plan is built around the central hypothesis that PARP inhibition will prove efficacious in the treatment of aggressive triple-negative breast cancer brain metastases, a disease for which systemic therapeutic options are limited. To test the hypothesis, a parallel clinical/pre-clinical approach will be employed. In Aim 1, the efficacy and safety of PARP inhibition, in combination with a chemotherapeutic active in breast cancer and known to traverse the blood brain barrier, to treat patients with triple-negative breast cancer brain metastases will be tested in a phase II, multi-center clinical trial. Nanoparticle formulations of anti-cancer agents enhance central nervous system delivery and are promising partners to couple with PARP inhibitors. Thus, Aims 2 and 3 are preclinical in nature and will test PARP inhibition in combination with several nanoparticle anti-cancer agents in an intracranial triple-negative breast cancer murine model. The candidate has assembled a mentorship team of internationally-recognized, independently-funded investigators with expertise in clinical/translational trial design (Carey), breast cancer biology (Carey, Perou), preclinical modeling (Perou, Sharpless, Miller) and nanoparticle pharmacology (Zamboni, Li, DiSimone) who will guide the candidate's research training and professional development in the collegial, productive and collaborative research environment of the SPORE-funded UNC Lineberger Comprehensive Cancer Center.