Immunomodulatory Effects of Targeting DNA Repair with Novel Temozolomide Combinations in Colorectal Cancer

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ABSTRACT DNA repair plays an important role in the pathogenesis of virtually all cancer types, and the identification of aberrant DNA repair pathways has identified predictive and prognostic biomarkers to targeted therapies. For example, epigenetic hypermethylation of the promoter of O6-methylguanine DNA methyltransferase (MGMT) predicts for better patient survival and increased sensitivity to temozolomide (TMZ) in multiple cancers, including colorectal cancer (CRC). TMZ is a monofunctional alkylator, and the DNA damage caused by TMZ is principally repaired by MGMT, which is silenced by promoter hypermethylation. The base excision repair (BER) pathway also serves as a critical pathway to repair TMZ DNA damage. Preclinically, the simultaneous inhibition of BER with polyp ADP ribose polymerase (PARP) inhibitors further sensitizes MGMT deficient tumors to TMZ. However, our preliminary findings reveal an alternative and parallel mechanism: TMZ damage causes acute replication stress and fork collapse leading to Ataxia Telangiectasia and Rad3 related (ATR) dependent phosphorylation of Checkpoint Kinase 1 (Chk1). We have leveraged these findings, and additional in vivo experiments, to advance novel TMZ combinations into the clinic with two investigator-initiated clinical trials for MGMT silenced CRC: 1) TMZ + olaparib (PARP inhibitor) and TMZ + AZD 6738 (ATR inhibitor). Enrollment will proceed at Yale Smilow Cancer Hospital with future opportunities expand to collaborating sites through our CRC Stand up to Cancer (SU2C) Dream Team. Furthermore, we aim to develop new biomarker assays including a biomarker assessing MGMT heterogeneity to identify tumors most sensitive to TMZ combinations, and perform genomic profiling. Leveraging DNA damage additionally represents a potential tool to stimulate an immune response, and through ancillary studies and using specimens obtained from our trials we will study the effects TMZ combinations on the immune microenvironment to lend support to the addition of immunotherapy in the future. I am a medical oncologist focusing on the treatment of advanced gastrointestinal (GI) cancers with an emphasis on innovative therapies for CRC. This award will facilitate my development as a physician- scientist equipped to design and conduct investigator-initiated early phase clinical trials based on innovative preclinical evidence regarding DNA repair and immunotherapies. My training will include didactic coursework for tumor immunology, practical experience of clinical trial implementation, and formal instruction in biomarker techniques. To achieve these goals, I have assembled a multidisciplinary mentorship team led by my primary mentor, Dr. Patricia LoRusso who has a proven track record of successfully mentoring junior faculty and extensive expertise in investigator-initiated clinical trials. At the conclusion of this award, I will have gained valuable skills into the underpinnings of clinical research generically, and specifically for clinical trial design, and biomarker identification for DNA repair and immunology. This award will help establish me as an independent investigator conducting early phase clinical trials for CRC and other GI cancers.