Project Grant K08CA283279

MOLECULAR DYNAMICS OF GLIOMA FORMATION AND DNA DAMAGE RESPONSE BY MUTANT IDH1 - PROJECT SUMMARY/ABSTRACT: GLIOMAS ARE THE MOST COMMON PRIMARY BRAIN TUMORS IN ADULTS, A SUBSET OF WHICH HAVE MUTATIONS IN THE METABOLIC GENE ISOCITRATE DEHYDROGENASE 1 (IDH1). CANCER-ASSOCIATED IDH1 MUTANTS (THE MOST COMMON OF WHICH IS IDH1R132H) ARE NEOMORPHS THAT PRODUCE THE ONCOMETABOLITE 2-HYDROXYGLUTARATE [(R)-2HG], WHICH IS THOUGHT TO CONTRIBUTE TO GLIOMA FORMATION. MUTANT IDH (MIDH) INHIBITORS THAT BLOCK (R)-2HG PRODUCTION HAVE BEEN RECENTLY SHOWN TO IMPROVE OUTCOMES IN LOWER-GRADE IDH-MUTANT GLIOMA PATIENTS AND ARE POISED TO BECOME STANDARD-OF- CARE. HOWEVER, RESPONSE TO MIDH INHIBITORS IS HETEROGENEOUS, AND OUR UNDERSTANDING OF HOW THESE DRUGS MAY WORK IN GLIOMA HAS BEEN SEVERELY LIMITED BY A LACK OF FAITHFUL ANIMAL MODELS OF LOWER-GRADE IDH-MUTANT GLIOMAS. IN AN EFFORT TO BETTER UNDERSTAND THESE UNANSWERED QUESTIONS REGARDING MIDH1 BIOLOGY, I MADE A GENETICALLY ENGINEERED MOUSE (GEM) MODEL OF MIDH1-DRIVEN GRADE 3 ASTROCYTOMA THAT CIRCUMVENTS KEY LIMITATIONS OF EXISTING MODELS AND PROVIDES THE OPPORTUNITY TO ADDRESS FUNDAMENTAL UNANSWERED QUESTIONS REGARDING MIDH BIOLOGY IN LOWER-GRADE GLIOMAS. I LEVERAGED THIS GEM AND OTHER MODELS TO SHOW THAT IDH-MUTANT GLIOMAS ARE SENSITIVE TO DE NOVO PYRIMIDINE SYNTHESIS INHIBITORS (E.G. DIHYDROOROTATE DEHYDROGENASE (DHODH) INHIBITORS) DUE TO AN INCREASED SUSCEPTIBILITY OF IDH-MUTANT CELLS TO DNA DAMAGE CAUSED BY THESE DRUGS. HOWEVER, WHETHER THIS SENSITIVITY TO DNA DAMAGE EXTENDS TO OTHER STANDARD-OF-CARE THERAPIES, AND THE MECHANISMS UNDERLYING THESE EFFECTS, IS NOT FULLY UNDERSTOOD. MY OVERALL OBJECTIVE IS TO LEVERAGE THE KEY ADVANTAGES OF MY GRADE 3 IDH-MUTANT GEM TO ADDRESS FUNDAMENTAL QUESTIONS REGARDING MUTANT IDH IN GLIOMA: I WILL DETERMINE THE RESPONSE OF MY GEM MODEL TO MIDH INHIBITORS AND EVALUATE MOLECULAR SIGNATURES OF MIDH INHIBITOR TREATMENT, DETERMINE WHETHER MIDH INHIBITORS AND/OR DHODH INHIBITORS ALTER RESPONSE TO RADIATION, AND IDENTIFY MECHANISMS UNDERLYING HOW IDH-MUTANT GLIOMAS RESPOND TO DNA DAMAGING TREATMENTS. I AM A RADIATION ONCOLOGIST WITH A RESEARCH BACKGROUND IN GLIOMA BIOLOGY AND A LONG-TERM GOAL OF DIRECTING MY OWN INDEPENDENT LABORATORY AS AN ACADEMIC PHYSICIAN SCIENTIST. I AIM TO FOCUS MY RESEARCH ON UNDERSTANDING THE MECHANISMS DRIVING GLIOMA GROWTH, WITH THE GOAL OF HARNESSING THIS KNOWLEDGE TO DEVELOP NOVEL THERAPEUTIC STRATEGIES. I AM CONDUCTING RESEARCH IN THE LABORATORY OF DR. WILLIAM G. KAELIN, JR., MD AT DANA-FARBER CANCER INSTITUTE (DFCI), WHICH I WILL CONTINUE DURING MY PROPOSED K08 RESEARCH. AS AN INSTRUCTOR, 80% OF MY TIME IS SPENT ON RESEARCH IN THE KAELIN LAB AND 20% IS ON PATIENT CARE TREATING PATIENTS WITH GLIOMA TUMORS. I HAVE ASSEMBLED AN EXPERT SCIENTIFIC ADVISORY COMMITTEE TO HELP GUIDE MY RESEARCH AND CAREER DEVELOPMENT: (1) DR. STEPHEN ELLEDGE, PHD (HARVARD MEDICAL SCHOOL), (2) DR. ALAN D'ANDREA, MD, (DFCI), (3) DR. BRADLEY BERNSTEIN, MD/PHD (DFCI), AND (4) DR. SAMUEL MCBRAYER, PHD (UT SOUTHWESTERN). MY CLINICAL MENTORS ARE DR. PATRICK WEN AND DR. DAPHNE HAAS-KOGAN, BOTH WORLD LEADERS IN NEURO-ONCOLOGY. MY TRAINING IN THIS ENVIRONMENT WILL BE OUTSTANDING PREPARATION TO ACHIEVE MY LONG-TERM CAREER GOALS AS AN INDEPENDENT INVESTIGATOR.