Project Grant R01NS137577

NEXT GENERATION ONCOLYTIC VIROTHERAPY TARGETING AKT AND ERK SIGNALING IN GLIOMA - ABSTRACT: THE OVERALL GOAL OF THIS PROJECT IS TO DEVELOP A NOVEL ONCOLYTIC VIRAL THERAPY FOR GLIOBLASTOMA (GBM). GBM IS THE MOST LETHAL AND FREQUENT PRIMARY ADULT BRAIN TUMOR WITH MEDIAN OVERALL SURVIVAL OF LESS THAN 21 MONTHS. AROUND 80 PERCENT OF GBM PATIENTS EXPERIENCE ONE OR MORE SEIZURES. INTERESTINGLY, EVERY FOURTH CASE OF GBM IS DIAGNOSED AFTER THE FIRST SIGN OF SEIZURE AS THE PRESENTING SYMPTOM. WE ALREADY OBSERVED SEIZURES IN OUR GBM MICE MODELS AND WILL EVALUATE SEIZURE FREQUENCY IN UNTREATED AND OHSV TREATED GBM MICE AS DESCRIBED. HERE WE PROPOSE TO CREATE AN ONCOLYTIC VIRUS THAT CAN SHOW IMPROVED EFFICACY ALONE AND IN COMBINATION WITH RADIATION AND TEMOZOLOMIDE. FURTHER WE BELIEVE THAT THE PROPOSED VIRUS MAY ALSO HELP ALLEVIATE GLIOMA ASSOCIATED EPILEPSY AND CAN IMPROVE QUALITY OF LIFE FOR PATIENTS. ONCOLYTIC VIRAL THERAPY WORKS BY LYSING TUMOR CELLS AS WELL AS ACTIVATING ANTITUMOR IMMUNITY. IN OUR PRELIMINARY RESULTS, WE CREATED AN OHSV THAT IS ARMED WITH PTENA (OP10/ OHSVP10). THIS VIRUS BLOCKS PI3K/AKT SIGNALING AND HAS INCREASED THERAPEUTIC EFFICACY THAT IS DEPENDENT ON T CELL ACTIVATION (RUSSELL ET AL NAT. COMMUN. 2018). LONG-TERM SURVIVORS IN THIS STUDY REJECTED SUBSEQUENT CHALLENGE AND THE THERAPEUTIC BENEFIT WAS LOST WHEN MICE WERE DEPLETED OF T CELLS. WE HAVE BEEN INVESTIGATING CHANGES INDUCED BY OP10 IN THE TUMOR AND TUMOR MICRO- ENVIRONMENT TO EXPLORE OPPORTUNITIES TO IMPROVE THE THERAPEUTIC INDEX OF THIS VIRUS FOR GBM. OUR STUDIES SHOW THAT OP10 INDUCES SECRETION OF HYLAURONIC ACID, WHICH FORMS THE MAJOR EXTRACELLULAR MATRIX (ECM) IN THE BRAIN. TO INVESTIGATE THE IMPACT OF THIS ON VIROTHERAPY WE HAVE CREATED A SECOND VIRUS CALLED OX44 THAT CAN BLOCK HA INDUCED SIGNALING IN BRAIN TUMORS. HERE WE WILL EVALUATE THE IMPACT OF COMBINING THESE TWO STRATEGIES ON THERAPEUTIC EFFICACY: ANTI-TUMOR KILLING AND IMMUNITY ALONE ( ), AND IN COMBINATION WITH RADIATION AND TEMOZOLOMIDE ( ). OUR STUDIES FURTHER SHOW THAT THIS STRATEGY CAN REDUCE THE EXPRESSION OF XCT, A AIM 1 AIM 2 TRANSPORTER IMPLICATED IN GLUTAMATE RELEASE. EXTRACELLULAR GLUTAMATE HAS BEEN SHOWN TO INDUCE GLIOMA GROWTH AND EPILEPSY, THUS WE HYPOTHESIZE THAT THIS STRATEGY WILL REDUCE EXTRACELLULAR GLUTAMATE AND ALSO REDUCE GLIOMA INDUCED EPILEPTIC SEIZURES. WE WILL THUS COLLABORATE WITH DR. DEAK AT AUGUSTA UNIVERSITY TO EVALUATE THE IMPACT OF THIS STRATEGY ON GLIOMA INDUCED EPILEPSY ( AIM 3 ).