Improving the therapeutic efficacy of chemoradiation by targeting the DNA damage response

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ABSTRACT There is an urgent need to improve the efficacy of chemoradiation therapy for patients with locally advanced cancers. Since unrepaired DNA double strand breaks (DSB) are the primary lesions responsible for the therapeutic efficacy of chemoradiation therapy, targeting cellular DNA damage response (DDR) pathways to prevent efficient DNA repair is a promising approach to enhance the efficacy of chemoradiation therapy. Defects in the DDR occur in a majority of cancers, suggesting targeted inhibition of the DDR would also provide an opportunity to selectively enhance sensitivity to chemoradiation in tumor compared to normal cells. Furthermore, our recent data demonstrate that DDR inhibition synergizes with radiation to confer sensitivity to immune checkpoint blockade (ICB) therapy. My training in cancer and radiation biology and pharmacology as well as my collaborations with Dr. Ted Lawrence and other physician-scientists at the University of Michigan make me uniquely well-qualified to develop innovative therapies combining DDR inhibitors, ICB and radiation. My effort is currently funded by U01 CA2166449 entitled, “Sensitization to chemoradiation by therapeutic targeting of the DNA damage response.” The overall goals of this project are to 1) evaluate DDR inhibitory drugs for their ability to modulate the cellular response to radiation-induced DNA damage and sensitize tumor cells to standard of care chemoradiation therapy 2) develop viable biomarkers for target engagement and/or therapeutic response and 3) translate our preclinical findings to rationally-designed clinical trials. As my research focus has evolved from antimetabolite-induced cell cycle checkpoints to targeted inhibition of DNA repair pathways, exploitation of replication stress and most recently anti-tumor immunotherapy, 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 in skin biopsies; DNA fiber combing to assess replication stress; and patient-derived xenograft based 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 modulation of the DDR to therapeutic response and translating those results to the development of viable biomarkers for both target engagement and therapeutic efficacy as evidenced by our recently completed clinical trial. This award will enable me to continue the preclinical development of DDR inhibitors and ICB in combination with radiation therapy that will inform future clinic trials for patients with locally advanced cancers.