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.