Cooperative Agreement UG3CA290375

DISCOVERY OF NOVEL NATURAL TEAD INHIBITORS FOR THE CHEMOPREVENTION OF LIVER TUMORS - PROJECT SUMMARY/ABSTRACT HEPATOCELLULAR CARCINOMA (HCC), THE MOST COMMON TYPE OF PRIMARY LIVER CANCER, IS A DIFFICULT DISEASE TO TREAT AND A LEADING CAUSE OF CANCER DEATHS WORLDWIDE WITH INCREASED INCIDENT RATE IN THE US. HCC HAS WELL CHARACTERIZED RISK FACTORS: CHRONIC HEPATITIS B VIRUS (HBV) OR HEPATITIS C VIRUS (HCV) INFECTION, LIVER CIRRHOSIS AND NON-ALCOHOLIC STEATOHEPATITIS (NASH), WHICH ACCOUNT FOR OVER 85% OF ALL HCC CASES. SUCH WELL-DEFINED POPULATION MAKES HCC AN IDEAL TYPE OF MALIGNANCY FOR CHEMOPREVENTION. HOWEVER, CURRENTLY THERE IS NO PREVENTION-INTERCEPTION DRUGS AVAILABLE FOR HCC. HENCE, THERE IS AN IMMINENT NEED TO DEVELOP EFFECTIVE AGENTS TO PREVENT AND INTERCEPT LIVER CANCER. HIPPO PATHWAY AND ITS TRANSCRIPTIONAL REGULATORS TEA DOMAIN TRANSCRIPTION FACTORS (TEAD) AND YAP/TAZ COMPLEXES HAVE BEEN SHOWN TO PLAY IMPORTANT ROLES IN TUMORIGENESIS. STUDIES FROM OUR AND OTHER LABS HAVE DEMONSTRATED THE KEY ROLES OF HIPPO PATHWAY IN HCC PATHOGENESIS. THEREFORE, TARGETING TEAD-YAP/TAZ COMPLEX COULD BE AN EFFECTIVE STRATEGY FOR HCC PREVENTION. OUR LONG-TERM GOAL IS TO IDENTIFY NOVEL HCC-PREVENTIVE NATURAL PRODUCTS (NPS) FROM UNDER- EXPLORED HAWAIIAN MICROORGANISMS AND OTHER NATURAL SOURCES. THE OBJECTIVE OF THIS PROPOSED RESEARCH IS TO DISCOVER NPS THAT INHIBIT TEAD PALMITOYLATION FOR THE PREVENTION AND INTERCEPTION OF HCC. THE CENTRAL HYPOTHESIS IS THAT THE UNDER-EXPLORED HAWAIIAN MICROORGANISMS AND NCI-NPS ARE EXCELLENT SOURCES FOR NEW CANCER PREVENTIVE NP DISCOVERY INCLUDING TEAD-P INHIBITORS. THE RATIONALE OF THE PROPOSED RESEARCH IS THAT ONCE NOVEL POTENT TEAD PALMITOYLATION INHIBITORS ARE IDENTIFIED, LEAD COMPOUNDS WILL BE STUDIED FOR THEIR MECHANISMS OF ACTION AND TESTED IN VIVO IN THE FOLLOW-UP STUDIES. THE OBJECTIVES OF THIS PROJECT WILL BE ACCOMPLISHED BY TWO SPECIFIC AIMS: (1) IDENTIFY HCC RELEVANT TEAD ISOFORM(S), IMPLEMENT BIOASSAY DEVELOPMENT, AND PERFORM A PILOT NP SCREENING; (II) PERFORM HTS, BGS, AND STRUCTURE DETERMINATION OF ACTIVE COMPOUNDS IN VITRO AND IN VIVO. THE PROPOSED PROJECT IS SIGNIFICANT AND HIGHLY TRANSLATIONAL BECAUSE THIS MULTI-PI GRANT AIMS AT IDENTIFYING NOVEL NPS WHICH INHIBIT TEAD PALMITOYLATION FOR HCC PREVENTION AND INTERCEPTION. THE RESULTS WILL LIKELY LEAD TO NEW CHEMOPREVENTION TRIALS TO INVESTIGATE THESE NEW NPS IN HIGH-RISK HCC POPULATION. THIS WOULD HAVE A PROFOUND EFFECT TO REDUCE THE BURDEN OF HCC ALL OVER THE WORLD.