Improving the efficacy of radiotherapy by targeting the DNA damage response, tumor immunology and tumor metabolism

Abstract public domain (NIH RePORTER)

There is an urgent need to improve the efficacy of radiation therapy (RT) for patients with locally advanced cancers. Our work focuses on three major mechanisms of tumor radioresistance: efficient DNA repair, unique tumor metabolism and lack of tumor immunogenicity. Our recently published studies demonstrate that direct inhibition of the DNA damage response (DDR) synergizes with radiation to confer tumor sensitivity to immune checkpoint blockade therapy. In addition, our preliminary data suggest that targeting tumor-specific metabolic pathways may indirectly inhibit repair of radiation-induced DNA damage and selectively radiosensitize tumor cells. My experience in cancer and radiation biology and pharmacology as well as my collaborations with Dr. Meredith Morgan, an expert in the fields of radiation biology and tumor immunology, and other physician- scientists at the University of Michigan, make me uniquely well-qualified and positioned to further develop innovative RT-combination therapeutics including combination with chemotherapy, molecularly targeted therapy, and immunotherapy. My research effort is currently directed towards P50 CA269022 (Morgan, Lawrence), “Molecularly Targeted Radiosensitization of Locally Advanced Cancers.” My original application focused primarily on optimizing therapeutic strategies that directly radiosensitize pancreatic adenocarcinoma (PDAC) through inhibition the DDR, specifically either ATM or PARP, and culminated in an ongoing phase I clinical trial (NCT05411094). This current application expands on the concept that direct inhibition of DNA repair induces both tumor radiosensitization and anti-tumor immune responses, to include inhibition of tumor-specific metabolic pathways that may also induce lethal DSBs and be therapeutic in combination with RT. As my research focus has evolved from antimetabolite-induced cell cycle checkpoints to targeted inhibition of DNA repair pathways, anti-tumor immunotherapy and exploitation of metabolic differences between normal and tumor cells, I have mastered a wide variety of state-of-the-art methodologies that have allowed me to critically assess the key determinants of therapeutic response including: flow cytometry and sorting for single cell protein analysis; confocal microscopy to track protein activation and localization at sites of DNA DSBs; immunohistochemistry to verify pharmacodynamic target inhibition; DNA fiber combing to assess replication stress; and both patient- derived xenograft based models and mouse syngeneic models of tumor response, including their treatment with CT and bioluminescence image-guided conformal radiation. Furthermore, I am adept at developing complementary genetic and pharmacological models to critically assess the relative contributions of changes in tumor metabolism and modulation of the DDR to immunogenic radiosensitization. Our ongoing mechanistic studies to better understand the interactions between tumor metabolism, radiation-induced DNA damage and immune checkpoint therapies, and, further, how these mechanisms relate to tumor cell-selective cytotoxicity, are instrumental to the rational, science-based design of future clinical trials.

Public health relevance public domain (NIH RePORTER)

There is an urgent need to improve radiation therapy for patients with locally advanced cancers such as pancreatic cancer or pediatric high-grade glioma, diseases which are increasingly common and difficult to cure. My work focuses on three major mechanisms of radiation resistance: efficient DNA repair, lack of immunogenicity and unique tumor metabolism. Understanding these mechanisms of resistance and their co-dependencies could have broad applications to the entire field of radiation-based therapeutics including combination with chemotherapy, molecularly targeted therapy and immunotherapy.