Tunneling Nanotube Inhibitors for Cancer Immunotherapy

Project Summary Prostate cancer (PCa) is the second-most common cancer in American men1. Early diagnosis and advances in therapeutic strategies have significantly improved overall survival; however, therapeutic resistance and cancer cell metastasis remain a challenge. Indeed, the development of castration-resistant prostate cancer (CRPCa),

an aggressive form of PCa after Androgen Deprivation Therapy (ADT) portends a poor prognosis, with overall survival standing at 1.5-years. The overall goal of our laboratory research is to develop bioengineered tools for targeted cancer therapy. We recently discovered the existence of tunnelling nanotubes (TNTs) between breast/prostate cancer cells and

endothelium that promote phenotypic changes allowing for increased metastasis7. These TNTs are actin mediated and inhibition of Sec3, an exocyst complex, inhibited their formation and consequent alteration of cancer cells into an aggressive phenotype. We then discovered that there further exists intercellular nanotubes

between breast cancer cells and natural killer T cells that hijack mitochondria, consequently dampening the immune response. This mechanism, we postulate, could be one of many that lower the efficacy of immunotherapy for cancers, necessitating research into its pathophysiology and consequent identification of

pharmacological target(s) For PCa, we propose investigating the existence of TNTs and their inhibitors in improving response. We will utilize Field Emission Scanning Electron and Confocal Microscopy to investigate TNTs in PCa/CRPCa cell lines LNCaP, PC3 co-cultured with effector murine CD8, NK T-cells; before probing human PCa tissue patient derived

xenograft (PDX) models. We will then establish the role of endosidins, novel exocyst complex inhibitors, in ameliorating TNT formation and hence mitochondrial transfer in the above models. The expected outcomes of this research are evaluation of a novel therapeutic class of drug against PCa/CRPCa cells at least via inhibition

of TNTs. Its result will offer a synergistic tool in promoting immune mediated control of tumors, at least in PCa/CRPCa progression. The broader positive impact of this project is to promote efficacy of current immunotherapy efforts in PCa/CRPCa.