Project Grant R01CA279528

ELUCIDATING THE ROLE OF TRYPTOPHAN HYDROXYLASE 1 IN NEUROENDOCRINE PROSTATE CANCER - PROJECT SUMMARY/ABSTRACT: NEUROENDOCRINE PROSTATE CANCER (NEPC) IS A FATAL PROSTATE CANCER (PC) SUBTYPE WITH AGGRESSIVE CLINICAL FEATURES AND A POOR PROGNOSIS. ALTHOUGH IT RARELY OCCURS DE NOVO, TREATMENT-INDUCED NEPC SHOWS A SIGNIFICANTLY INCREASING INCIDENCE AFTER WIDESPREAD USE OF MORE POTENT ANTIANDROGENS FOR TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER (CRPC) IN RECENT YEARS, CONSTITUTING UP TO 25% OF ADVANCED THERAPY- RESISTANT CRPC. CURRENTLY, NEPC REMAINS INCURABLE WITH A MEDIAN OVERALL PATIENT SURVIVAL OF LESS THAN A YEAR FROM TIME OF DIAGNOSIS. THESE DISMAL FACTS UNDERSCORE A PRESSING CLINICAL NEED TO IDENTIFY NEW MOLECULAR DETERMINANTS OF NEPC PATHOGENESIS AND PROGRESSION AND DEVELOP AN EFFECTIVE TARGETED THERAPY TO PROLONG SURVIVAL. IN PRELIMINARY STUDIES, WE FOUND THAT TRYPTOPHAN HYDROXYLASE 1 (TPH1), THE RATE-LIMITING ENZYME RESPONSIBLE FOR BIOSYNTHESIS OF PERIPHERAL SEROTONIN KNOWN AS A NEUROTRANSMITTER ENRICHED IN NEUROENDOCRINE TUMORS AND A CLASSICAL NEUROENDOCRINE BIOMARKER, IS CRITICALLY REQUIRED FOR MAINTAINING NEPC DIFFERENTIATION, DEVELOPMENT AND GROWTH. GENETIC OR PHARMACOLOGICAL INHIBITION OF TPH1 IN NEPC CELLS PROFOUNDLY REPRESSES NEUROENDOCRINE MARKERS, CELL PROLIFERATION AND INVASION, AND XENOGRAFT TUMOR GROWTH IN MICE. IMPORTANTLY, OUR DATA SHOWED THAT TPH1 IS UPREGULATED IN HUMAN NEPC AND CRPC CARRYING NEUROENDOCRINE FEATURES RELATIVE TO PROSTATIC ADENOCARCINOMA IN MULTIPLE INDEPENDENT PATIENT COHORTS. MECHANISTICALLY, OUR TRANSCRIPTOMIC, BIOINFORMATIC AND BIOCHEMICAL ANALYSES DEMONSTRATED THAT TPH1 ACTIVATES MTOR SIGNALING AND SUBSEQUENTLY E2F1 AND A NEPC-PROMOTING ONCOGENIC TRANSCRIPTIONAL PROGRAM MEDIATED SYNERGISTICALLY BY FOXM1 AND TAZ. THESE NEW FINDINGS SUPPORT OUR HYPOTHESIS THAT TPH1 PLAYS AN ACTIVE ROLE DRIVING NEPC AND REPRESENTS A THERAPEUTIC TARGET OF NEPC. TO TEST THIS HYPOTHESIS, AIM 1 WILL DELINEATE THE MOLECULAR MECHANISM OF TPH1 SIGNALING IN NEPC, SPECIFICALLY DISSECTING HOW TPH1 ACTIVATES THE MTOR-FOXM1/TAZ/E2F1 SIGNALING AXIS AND HOW THIS AXIS CONFERS NEPC GROWTH ADVANTAGES AND NEUROENDOCRINE TRAITS IN THE CONTEXT OF TPH1. WE WILL ALSO ESTABLISH THE CLINICAL RELEVANCE OF OUR MECHANISTIC FINDINGS AND ASSESS THEIR PROGNOSTIC VALUE IN A LARGE COLLECTION OF HUMAN ADVANCED PC SAMPLES. AIM 2 WILL DEFINE THE FUNCTIONAL AND BIOLOGICAL IMPACT OF TPH1 ON NEPC DIFFERENTIATION, GROWTH AND PROGRESSION USING A SERIES OF IN VITRO AND IN VIVO PHENOTYPIC AND PHARMACOLOGICAL ASSAYS COUPLED WITH COMPLEMENTARY HUMAN AND MOUSE NEPC CELLS AND ORGANOIDS, CELL LINE- AND PATIENT-DERIVED XENOGRAFT MOUSE MODELS, AND TRAMP TRANSGENIC MICE. SUCCESSFUL COMPLETION OF THIS PROJECT WILL GREATLY DEEPEN OUR MECHANISTIC UNDERSTANDING OF NEPC DEVELOPMENT AND PROGRESSION AND PROVIDE A COMPELLING RATIONALE FOR REPURPOSING CLINICALLY AVAILABLE TPH1 INHIBITORS FOR NEPC THERAPY WITH QUICK TRANSLATIONAL POTENTIAL TO BENEFIT LATE-STAGE PC PATIENTS IN THE NEAR FUTURE.