Neuroendocrine Prostate Cancer Progression and Novel Therapeutic Vulnerabilities

About This Grant

Neuroendocrine prostate cancer (NEPC) has long been considered a rare and largely unrepresentative variant of prostate cancer (PrCa), lacking canonical disease traits, such as androgen dependence. This perspective, however, has now evolved. First, NEPC is not as rare as previously thought. This condition arises in at least a quarter of all PrCa patients that progress after androgen suppression therapy, and its incidence is only bound to increase as ever more potent androgen-targeting modalities are introduced in the clinic. Second, NEPC is not merely an example of cancer drug resistance. Instead, it is the result of the extraordinary plasticity of tumor cells, which adapt to the evolutionary pressure imposed by therapy by rewiring transcriptional and metabolic networks, changing lineage specification, and reprogramming the microenvironment. The outcome is a rapidly progressing condition, quick to metastasize to bone and visceral organs, in essence insensitive to therapy and carrying a life expectancy of 7 months or less. Although NEPC is clearly an urgent and expanding medical condition, its pathophysiology has remained elusive: what drives the acute metastatic propensity in these patients is unknown and novel, actionable therapeutic targets have not been identified. The present Program is designed to bridge this knowledge gap and define the mechanistic and translational landscape of NEPC by pursuing three overarching goals: (i) elucidate the mechanisms of NEPC metastasis; (ii) unravel how immune-inflammatory reprogramming of the microenvironment shapes NEPC progression; and (iii) credential novel therapeutic vulnerabilities exposed by NEPC plasticity. To accomplish these objectives, the Program aligns three highly integrated Projects and a research enhancer Core into a single scientific continuum. Project 1 (Drs. Languino and Kelly) will characterize how signaling by small extracellular vesicles (sEV) stimulates NEPC motility and sustains pro-tumorigenic intercellular communication; Project 2 (Drs. Altieri and Fatatis) will focus on mitochondrial dysfunction and aberrant IL-1â production as novel determinants of NEPC metastasis and actionable therapeutic vulnerabilities; and Project 3 (Dr. Goodrich) will map the metabolic and inflammatory landscape of NEPC resulting from ubiquitous loss of the RB1 tumor suppressor. Fully embedded in the specific aims, an Administration and Data Science Core (Core A) will ensure scientific integration, biostatistics and bioinformatics support, administrative and financial coordination, and community outreach efforts focused on PrCa racial disparities. Although this is a new resubmission, Program investigators have a long track record of collaborative achievements in PrCa research: they led an earlier program project grant for 11 years (P01 CA140043; Novel Molecular Therapies of Prostate Cancer), jointly published over 100 peer-reviewed articles, and brought a new, first-in-human anticancer agent to the clinic (ClinicalTrials.gov NCT04827810). Together, the Program is uniquely poised to bring practice changing mechanistic and preclinical advances to improve the currently abysmal outlook of NEPC patients in the clinic.