Investigating replication GAP suppression in distinct modelsof chemoresistant brca mutant cancers

The National Cancer Institute awarded the University of Massachusetts Medical School $136,840 on December 1, 2025, under the Cancer Research Manpower program (CFDA 93.398) to investigate replication gap suppression in chemoresistant BRCA mutant cancers.

The award funds research into the factors contributing to chemoresistance in BRCA1 and BRCA2 mutant hereditary breast and ovarian cancers. The work addresses a critical clinical problem: tumors frequently develop resistance to current chemotherapy and poly(ADP-ribose) polymerase inhibitor treatments. The investigator proposes two aims. Aim 1 determines whether an axis of chemoresistance in BRCA1-deficient cancers linked to restored homologous recombination is instead mediated by single-stranded DNA gap suppression. Aim 2 investigates whether gap suppression in a chemoresistant BRCA2 tumor model links to translesion synthesis activation and how translesion synthesis can be overcome to resensitize these cancers. The research seeks to identify druggable targets and biomarkers for personalized chemotherapy, potentially reducing the side-effect burden of existing chemotherapies and improving patient outcomes.

Performance occurs in Worcester, Massachusetts through May 11, 2028. The Cancer Research Manpower program supports biomedical training opportunities for individuals pursuing careers in basic, clinical, and prevention research important to the National Cancer Program.

Abstract

The overall goal of this proposal is to gain a new understanding of the factors that contribute to chemoresistance in BRCA1 and BRCA2 (brca) mutant hereditary breast and ovarian cancers (hboc). Currently clinical strategies rely on chemotherapies and poly (ADP-ribose) polymerase inhibitors to control malignant disease. Unfortunately, tumor chemoresistance frequently occurs which necessitates studies that uncover the critical factors leading to chemoresistance. We have recently discovered chemoresistance is linked the single-stranded (SS)DNA GAP suppression in multiple models of hbocs and patient tumors. Our work has generated a paradigm shift that ssdna predicts sensitivity whereas GAP suppression predicts resistance. To expand upon our model that ssdna gaps are the sensitizing lesions in brca cancers, i propose two aims. In aim 1, i will determine if an axis of chemoresistance in BRCA1 deficient cancers, linked to restored homologous recombination, is instead mediated by GAP suppression. In aim 2, i will determine if GAP suppression in a chemoresistant BRCA2 tumor model is linked to the activation of translesion synthesis and how translesion synthesis can be overcome to resensitize these cancers. Together, these aims increase our knowledge of the basic factors that lead to chemoresistance in the clinic and will provide new insights into the vulnerabilities unique to brca deficient cancers. Moreover, by identifying unique factors contributing to chemoresistance, we will develop an understanding for potential druggable targets and biomarkers for future personalized chemotherapy. Existing chemotherapies are constrained by their side-effect profiles, often taxing patients' tolerance and potentially inducing secondary malignancies. Generating a new understanding of the factors contributing to chemoresistance is pertinent to improving patient outcomes.