Exploiting Synthetic Lethality with IDH1 Mutations to Improve Brain Tumor Therapy
Malignant gliomas are notoriously refractory to therapy and there is a dire unmet need for new treatments. Discovery of the high prevalence of IDH1 mutations in lower grade gliomas and secondary glioblastomas has opened new avenues for therapeutic intervention, including the use of direct inhibitors of mutant IDH1 enzymes. An alternative approach to treating these brain tumors entails the exploitation, rather than inhibition, of IDH1 mutant enzymes through the discovery of associated synthetic lethal interactions. Our previous work describing nitrogen metabolism reprogramming by IDH1 mutations led to the development of a new synthetic lethality-based treatment strategy that is currently being tested in a Phase I trial for glioma patients (NCT03528642).
We are pursuing both hypothesis-driven and unbiased approaches to identify additional synthetic lethal interactions with the canonical IDH1 R132H oncogene. Because radiation is a cornerstone of the standard-of-care treatment protocol for glioma, we are particularly interested in discovering collateral vulnerabilities induced by IDH1 mutations that impact radiosensitivity. To evaluate the translational relevance of our findings, we use patient-derived and genetically engineered mouse models of glioma to conduct preclinical efficacy studies. Our long-term goal is to lay the basic and translational scientific groundwork needed to support clinical testing of new glioma treatment strategies using IDH1 mutations as predictive biomarkers.