Project Grant F31CA306268

TARGETING ALC1 ATPASE ACTIVITY AS A NEW SYNTHETIC LETHAL STRATEGY FOR BRCA-MUTANT CANCERS - PROJECT SUMMARY BREAST CANCER GENES 1/2 (BRCA1/2) PROTEINS ARE ESSENTIAL COMPONENTS OF AN ERROR-FREE DNA DOUBLE- STRAND BREAK (DSB) REPAIR PATHWAY CALLED HOMOLOGOUS RECOMBINATION (HR). THEREFORE, LOSS-OF-FUNCTION MUTATIONS IN BRCA1/2 OR OTHER HR GENES CONFERS A STRONG DISPOSITION FOR CANCER DEVELOPMENT. THIS IS PARTICULARLY EVIDENT IN MALIGNANCIES AFFECTING WOMEN, WHEREBY MUTATIONS IN BRCA1/2 CONFER A ~10-46% AND 45-89% INCREASED RISK OF OVARIAN AND BREAST CANCERS, RESPECTIVELY. SYNTHETIC LETHALITY BETWEEN POLY (ADP-RIBOSE) POLYMERASE INHIBITORS (PARPI) AND BRCA1/2 MUTATIONS PROPELLED THE FDA-APPROVAL OF MULTIPLE PARPI FOR THE TREATMENT OF PATIENTS WITH BRCA-MUTANT CANCERS. DESPITE A PROMISING INITIAL CLINICAL RESPONSE OBSERVED WITH PARPI, THE EMERGENCE OF RESISTANCE TO THESE DRUGS DURING TREATMENT IS COMMON. FURTHERMORE, SEVERE SIDE EFFECTS AND THE DEVELOPMENT OF SECONDARY MALIGNANCIES ASSOCIATED WITH PARPI, LIMIT THE EFFICACY OF THIS THERAPEUTIC STRATEGY. THIS PAUCITY OF TARGETED THERAPEUTIC OPTIONS FOR BRCA-MUTANT CANCERS NECESSITATES THE DEVELOPMENT OF NEW SYNTHETIC LETHAL THERAPEUTIC APPROACHES THAT HAVE DURABLE EFFICACY AS A SINGLE AGENT. THIS PROPOSAL AIMS TO ESTABLISH A NEW MECHANISM-BASED SYNTHETIC LETHAL APPROACH FOR HR/BRCA-MUTANT CANCERS. THE RATIONALE FOR THIS PROPOSAL EMERGES FROM OUR UNPUBLISHED STUDIES THAT ATPASE-DEFICIENT MUTANTS OF A CHROMATIN REMODELING ENZYME, AMPLIFIED IN LIVER CANCER 1 (ALC1) RESULTS IN RAPID KILLING OF BRCA-MUTANT CELLS WITH NO IMPACT ON NORMAL HEALTHY CELLS. THIS OBSERVATION PROVIDES THE FOUNDATIONAL EVIDENCE THAT INHIBITORS ABROGATING THE ATPASE ACTIVITY OF ALC1 CAN HAVE SINGLE-AGENT ANTITUMOR ACTIVITY IN BRCA-MUTANT CANCERS. IN THIS PROPOSAL WE AIM TO DEFINE A FRAMEWORK FOR THE DEVELOPMENT OF ALC1 INHIBITORS. MORE SPECIFICALLY, WE WILL (I) DECIPHER THE MOLECULAR BASIS OF SYNTHETIC LETHALITY BETWEEN ALC1 ATPASE MUTANT AND BRCA-DEFICIENCY AND (II) DEFINE REGIONS IN ALC1 ATPASE DOMAIN THAT RENDER SYNTHETIC LETHALITY IN BRCA1/2-DEFICIENT SETTINGS. SUCCESSFUL COMPLETION OF THIS PROPOSAL WILL PROVIDE FUNDAMENTAL INSIGHTS INTO HOW ALC1 ATPASE ACTIVITY IS REGULATED AND WILL HELP DEVELOP A SAFE AND AN INNOVATIVE TARGETED THERAPEUTIC APPROACH FOR BRCA-MUTANT CANCERS. THESE PROPOSED AIMS CLOSELY ALIGN WITH MY STRONG INTEREST IN DEFINING WAYS BY WHICH DNA DAMAGE RESPONSE PATHWAYS CAN BE TARGETED FOR DEVELOPING NEW CANCER TREATMENTS. WORKING ON THIS PROPOSAL WILL HONE MY TECHNICAL SKILL SETS IN ADVANCED MOLECULAR AND BIOCHEMICAL APPROACHES, BIOINFORMATICS, FUNCTIONAL GENOMICS AND MOUSE MODELING. DURING THIS TRAINING PERIOD I WILL ALSO ACTIVELY PARTICIPATE IN SCIENTIFIC WRITING, PRESENTATIONS, MENTORING AND DEVELOPING LEADERSHIP SKILLS. THIS TRAINING WILL PROVIDE ME WITH SKILLS CRITICAL FOR MY TRANSITION TO A COMPETITIVE POSTDOCTORAL CANDIDATE AND SUBSEQUENTLY AS AN INDEPENDENT PRINCIPAL INVESTIGATOR DEVELOPING NEW APPROACHES TO PREVENT AND TREAT CANCERS.