Tumor-associated macrophage reprogramming through PARP14 inhibition in muscle-invasive bladder cancer

Dana-Farber Cancer Inst, Boston MA

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Abstract

Project summary This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-21-100. This NCI Early-stage Surgeon Scientist Program proposal for Dr. Filipe de Carvalho describes a research plan and career development program leading up to an academic career as an independent Urologic Oncologist surgeon-scientist investigator. Dr. De Carvalho is a urologist at Brigham and Women’s Hospital committed to an independent research career focused on accelerating the development of therapeutic strategies to target the immune-suppressive tumor microenvironment in bladder cancer. This Early-stage Surgeon Scientist Program will allow Dr. De Carvalho to become proficient in tumor-associated macrophage biology in bladder cancer with the ultimate goal of developing novel macrophage-directed therapeutic strategies for bladder cancer patients. Dr. De Carvalho will be mentored by Dr. Eliezer Van Allen and co- mentors Drs. Kent Mouw and Elizabeth Mittendorf, leaders in bladder cancer genomics and cancer immunology. Dr. Van Allen is Chief of Division of Population Sciences, Dana-Farber Cancer Institute, and has mentored over a dozen of young investigators that moved to successful independent academic positions. Dr. De Carvalho also gathered an outstanding scientific advisory committee and collaborators that excel in mouse models, statistics and cancer genomics to guide career development and scientific progress. The research proposal focuses on tumor-associated macrophages, which are immune cells with a critical role in tumor growth and immune evasion. Recent evidence revealed a therapy-induced conversion of normally anti-tumor TAMs to a tumor-permissive phenotype. The central hypothesis is that cisplatin induces chronic immunosuppressive IFN signaling in cancer cells leading to a TAM-infiltrated phenotype and immune evasion in treatment-resistant tumors. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the mechanism and effectiveness of targeting TAMs to improve sensitivity of bladder cancer to combined cisplatin and immune checkpoint inhibition. 2) Dissect the tumor-TAM crosstalk that mediates cisplatin resistance. These studies are expected to dissect how TAMs inhibit cytotoxic T-cells in cisplatin-resistant bladder cancer in territories of immune evasion across bladder tumors as well as position Dr. De Carvalho to submit a competitive R01 near the completion of this Program.