Project Grant R01DE034300

DUAL P300 AND P53 REACTIVATION IN HPV+ HEAD AND NECK CANCER - PROJECT SUMMARY INCIDENCE OF HPV+ OPC HAS BEEN INCREASING FOR SEVERAL DECADES AND THIS UPWARD TREND IS EXPECTED TO CONTINUE UNTIL AT LEAST 2060. CURRENT FIRST-LINE MODALITIES TO MANAGE HPV+ OPC PATIENTS ARE EFFECTIVE BUT NOT WITHOUT LIMITATIONS. A KEY EVENT IN HPV-DRIVEN TUMORIGENESIS IS THE INACTIVATION OF THE P53 TUMOR SUPPRESSOR PROGRAM. HPV ONCOGENE, E6, INACTIVATES P53 THROUGH TWO DISTINCT PATHWAYS: HPVE6 PROMOTES THE ASSEMBLY OF THE HPVE6-E6AP-P53 TRIMERIC PROTEIN COMPLEX RESULTING IN UBIQUITINATION AND DEGRADATION OF P53, AND HPVE6 DIRECTLY BINDS TO P300 TO BLOCK P300-DIRECTED ACETYLATION AND ACTIVATION OF P53. WE HYPOTHESIZED THAT DISRUPTING THE HPVE6-P300 INTERACTION WILL LIBERATE SUFFICIENT P300 TO RESTORE P53 AND P300 FUNCTIONALITY SIMULTANEOUSLY IN HPV+ OPC. OUR TEAM INITIATED A DRUG DISCOVERY PLATFORM TO TARGET THE HPVE6-P300 INTERACTION. OUR WORK SHOWED THAT IN HPV+ OPC MODELS: (A) HPVE6 BINDS TO THE CH1 DOMAIN OF P300, (B) OUR LEAD MOLECULE, OHM1, A CH1/P300 LIGAND, DISRUPTS HPVE6-P300 INTERACTION AND REACTIVATES P53 AND P300, (C) OHM1 IS ACTIVE IN VITRO AND IN VIVO, AND (D) CONCURRENT OHM1+CISPLATIN COMBINATION TREATMENT YIELDS DURABLE COMPLETE ANTI-TUMOR RESPONSES IN VIVO. OUR RESULTS ARE VERY COMPELLING AND, SUPPORTS FURTHER RESEARCH AND DEVELOPMENT OF DUAL P53 AND P300 REACTIVATION AS A THERAPEUTIC STRATEGY FOR HPV+ OPC. IN THIS PROJECT, WE PROPOSE TO EXTENSIVELY DETERMINE THE MECHANISMS OF ACTION OF P53 AND P300 REACTIVATION IN RESPONSE TO OHM1 IN HPV+ OPC. THE SPECIFIC AIMS ARE: (1) DETERMINE IF OHM1 MODULATES THE P53 POST-TRANSLATIONAL MODIFICATION CODE TO CONTROL P53 FUNCTIONALITY AND LEVELS, AND PROMOTE ANTI-CANCER ACTIVITY IN HPV+ OPC, (2) TO DETERMINE IF OHM1 RESHAPES THE TUMOR-MICROENVIRONMENT AND BOOST IMMUNOTHERAPY RESPONSE IN HPV+ OPC.