Project Grant R21CA286348

INHIBITION OF PLEIOTROPHIN TO COMBAT PANCREATIC CANCER METASTASIS - PROJECT SUMMARY PANCREATIC DUCTAL ADENOCARCINOMA (PDA) IS PROJECTED TO BECOME THE SECOND LEADING CAUSE OF CANCER-RELATED DEATHS IN THE UNITED STATES BY THE YEAR 2030 UNLESS SIGNIFICANT PROGRESS IS MADE ON IMPROVING THERAPY FOR THIS DISEASE. THE CURRENT 5-YEAR SURVIVAL RATE IS ~12%, SHOWING A MODEST INCREASE OVER THE LAST 30 YEARS. ALTHOUGH CHEMOTHERAPY RESPONSE RATES ARE IMPROVING, THESE SYSTEMIC THERAPIES ONLY PROVIDE MINIMAL SURVIVAL ADVANTAGE. IN ADDITION, PDA IS LARGELY RESISTANT TO IMMUNOTHERAPY. METASTASIS, A COMMON EVENT IN PDA PATIENTS, LIMITS THE UTILITY OF SURGICAL RESECTION, THE MOST EFFECTIVE THERAPEUTIC STRATEGY FOR PDA. UNDERSTANDING FACTORS THAT CONTRIBUTE PDA PROGRESSION AND METASTASIS HAS THE POTENTIAL TO REVEAL NOVEL THERAPEUTIC TARGETS. RECENTLY, WE HAVE SHOWN THAT AN EMBRYONIC NEUROTROPHIC FACTOR, PLEIOTROPHIN (PTN), MARKS SUCCESSFUL LUNG METASTASES IN MOUSE PRE-CLINICAL BREAST CANCER MODELS. CONSEQUENTLY, BLOCKING PTN, PHARMACOLOGICALLY OR GENETICALLY, REDUCES METASTASIS AND SENSITIZES METASTATIC BREAST CANCER TO CHECKPOINT BLOCKADE AND CHEMOTHERAPY. THE CURRENT PROPOSAL SEEKS TO DETERMINE WHETHER PTN INHIBITION IS THERAPEUTICALLY EFFICACIOUS IN PRECLINICAL MODELS OF PDA. PTN IS EXPRESSED IN PDA AND IS ASSOCIATED WITH DISEASE PROGRESSION. HOWEVER, THERE HAVE ONLY BEEN LIMITED EFFORTS TO PERTURB PTN FUNCTION IN MODELS OF PDA. WE HAVE THE TOOLS TO ADDRESS THE THERAPEUTIC UTILITY OF TARGETING PTN IN ROBUST MODELS OF PDA. THIS PROPOSAL IS DIRECTLY RESPONSIVE TO PAR-22-2216 WHICH CALLS FOR APPLICATIONS FOCUSED ON NOVEL STRATEGIES TO ENHANCE THE EFFECTIVENESS OF CHEMOTHERAPY AND OR IMMUNE THERAPY. SUCCESS IN COMPLETING THE AIMS OF THE PROJECT WILL NOMINATE PTN AS A NEW POTENTIAL TARGET FOR THE TREATMENT OF PDA.