Targeting Nucleotide Excision Repair Deficiency to Improve Bladder Sparing Treatment for Muscle Invasive Bladder Cancer

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PROJECT SUMMARY Organ-preserving therapy is the standard curative approach for numerous types of solid tumors. For patients with muscle-invasive bladder cancer (MIBC), bladder removal (radical cystectomy) and bladder-preserving chemoradiotherapy (CRT) are the two curative treatment approaches supported by long-term safety and efficacy data; however, these two approaches have never been compared in a randomized trial. Therefore, the decision between approaches is currently made based solely on clinical-pathologic features and patient/provider preference. There are currently no molecular biomarkers available to inform the decision between radical cystectomy and bladder-sparing CRT. Our previous work identified a subset of ~15% of MIBCs with somatic alterations in the nucleotide excision repair (NER) gene ERCC2. The NER pathway is a highly conserved DNA repair pathway that repairs bulky DNA adducts caused by genotoxins such as UV irradiation and platinum drugs. We showed that MIBC patients with ERCC2-mutant tumors have improved response to cisplatin-based chemotherapy compared to MIBC patients with wild-type (WT) ERCC2 tumors, and our functional work demonstrated that clinically observed ERCC2 mutations were unable to support normal cellular NER and were sufficient to confer increased cisplatin sensitivity in preclinical bladder cancer models. However, the impact of ERCC2 mutations on response to clinical CRT regimens is unknown. The overarching hypothesis of this proposal is that NER deficiency conferred by ERCC2 mutations define a subset of bladder tumors with unique biological properties and therapeutic vulnerabilities, including increased sensitivity to clinically relevant CRT regimens. The goal of work proposed here is to dissect the cellular mechanisms that contribute to the unique properties of NER deficient tumors and to define the impact of NER deficiency on CRT response. In Aim 1, we will investigate the association between mutations in ERCC2 and other NER pathway genes and clinical outcomes in a cohort of 240 MIBC patients treated with CRT on completed cooperative group trials. We will functionally interrogate the impact of observed NER gene alterations in bladder cancer models and we will compare the activity of commonly used CRT regimens in isogenic NER-proficient/deficient human bladder cancer preclinical models. In Aim 2, we will define the impact of NER deficiency on immune cell subsets in the bladder tumor microenvironment in two isogenic NER-proficient/deficient mouse bladder cancer models and we will investigate the contribution of CD8+ T cells to CRT response in the NER-proficient and NER-deficient models. We will also perform transcriptional profiling of 190 clinical MIBC cases and will investigate the relationship among ERCC2 mutation status, transcriptional signatures of immune infiltration, and clinical outcomes. In Aim 3, we will investigate CHK1 inhibition as a strategy to induce NER deficiency and increase sensitivity to cisplatin-based treatments in bladder tumors with WT ERCC2. Together, these integrated genomic and functional studies will define the impact of NER deficiency as a biomarker and therapeutic target in bladder-sparing treatment approaches for MIBC.