Investigation of Sirt1 activation to target IDH mutant glioma

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Project Summary IDH mutant gliomas are incurable, primary brain tumors that affect young to middle-aged adults and are defined by a mutation in a key metabolic gene. Despite treatment with surgery, radiation and chemotherapy, these gliomas exhibit unrelenting growth that ultimately leads to neurologic decline and premature death. Interestingly, many types of tumor cells, including IDH mutant glioma, reprogram metabolic processes to promote tumor growth. The overarching goal of this proposal is to target tumor-specific metabolic vulnerabilities to more effectively halt IDH mutant glioma growth. This is based on preliminary data demonstrating that activation of the critical metabolic regulator Sirt1, using Sirt1 activating compounds (STACs) or Sirt1 overexpression, leads to cytotoxicity in IDH mutant cells, leading to the hypothesis that IDH mutant glioma sensitivity to Sirt1 activation is related to IDH-induced metabolic rewiring. This five-year career development project is aimed at investigating the metabolic underpinnings and effectiveness Sirt1 activation in IDH mutant gliomas using orthotopic mouse models. This study will also determine the effectiveness of combining metabolic targeting with inhibition of the cell cycle, a strategy based on the premise that targeting both processes may achieve more effective tumor eradication. The first aim will test the anti-tumor effectiveness of STACs in combination with cell cycle inhibition using patient-derived, IDH mutant glioma lines implanted intracerebrally. The second aim will utilize RNA- sequencing to investigate the cellular processes influenced by STACs. The third aim will explore the ability of caloric restriction, known to exert longevity-promoting effects through Sirt1 upregulation, to enhance cell cycle inhibition and prevent glioma growth. Dr. Miller is a highly trained, passionate physician-scientist uniquely poised to make an impact on treatment for glioma. She is an Instructor of Neurology at Harvard Medical School in the Pappas Center for Neuro-Oncology at Massachusetts General Hospital. This K08 application is designed to build on previous cancer research experience to develop expertise in studying glioma biology. Her mentors, Drs. Cahill and Wakimoto, are leaders in the field of IDH mutant glioma metabolism and modeling. The proposed project will also utilize collaborations with established leaders in single-cell transcriptomics and metabolism. This expertise is complemented by the candidate’s scientific advisors, Dr. Brastianos and Dr. Batchelor, who are experts in translational Neuro-Oncology. This award will be further supported by the unparalleled institutional support and environment offered by Massachusetts General Hospital and Harvard Medical School. Dr. Miller’s future goal is to use the expertise gained during this award to study the effect of novel therapeutics in human patients with glioma. The K08 is an important stepping stone for building a translational research program in Neuro-Oncology and ultimately becoming an independent, R01-funded investigator.