Exploiting Homologous Recombination Defects with a Novel DNA-Crosslinking Strategy - The Bindra (sponsor) and Herzon (co-sponsor) Labs seek to exploit tumor-associated DNA repair defects to obtain clinically acceptable therapeutic indices with systematically administered genotoxic agents. In two recent publications, one of which I co-authored, we demonstrated that DNA-damaging agents can be chemically modified for enhanced activity against tumors cells with a specific DNA repair defect and iteratively refined for limited toxicity in normal cells. My proposal focuses on applying our laboratory’s DNA modification strategy to homologous recombination (HR) deficiency (HRD), one of the most common DNA repair defects in cancer. During my preliminary studies, I profiled a diverse range of clinically relevant DNA crosslinkers and PARPis for selectivity against BRCA2-deficient (HRD) cell lines, which identified CB1954 as a highly selective agent against HRD cell lines (e.g., IC50wt / IC50BRCA2-/- ≈ 500). Prior research focused on the enzymatic nitroreduction of CB1954 to create a therapeutic index in the clinic without consideration of the DDR phenotype of the tumor. I propose the tumor-specific, biomarker-driven application of CB1954 in the treatment of HRD tumors. Our objectives are to: (1) determine the structure-activity relationship of CB1954’s selectivity for HRD cells and (2) investigate the therapeutic potential of CB1954 using mouse tumor models. The rationale for the proposed research is that CB1954’s limited clinical efficacy was due to the lack of a tumor-specific biomarker conferring sensitivity, and we have identified such a potential biomarker that is common in the clinic. My career goal is to establish my own laboratory as an independent investigator at a major research institute. My research ambitions lie in the interaction of DNA-damaging agents, DNA repair, and cancer, the overlap of which has great therapeutic potential and plays a significant role in carcinogenesis. I aim to investigate this area by leading an interdisciplinary team of biologists and chemists with the sincere belief that a diversity of scientific and personal backgrounds leads to the greatest discoveries in science. This fellowship will help me achieve this goal via completion of the proposed research, academic, and leadership objectives. My research objectives include publication of the research described above as first-author, presenting this research at international conferences and internal seminars, and completion of my dissertation on the exploitation of the most common tumor-specific DNA repair deficiencies via the development of DNA-damaging agents. My academic objectives include an intensive Cold Springs Harbor Laboratory course on mouse models, writing and career development workshops, and at least two teaching fellowships. My leadership objectives include development of my role as the Pathology Department’s Chief Graduate Student and my role as a mentor to middle school and high school students pursuing higher education.
