Investigation of Sirt1 activation to target IDH mutant glioma

项目摘要 IDH突变型神经胶质瘤是一种无法治愈的原发性脑肿瘤，影响年轻人到中年人， 是由一个关键代谢基因的突变决定的尽管进行了手术、放疗和化疗， 这些神经胶质瘤表现出无情的生长，最终导致神经功能衰退和过早死亡。 有趣的是，许多类型的肿瘤细胞，包括IDH突变型胶质瘤，重新编程代谢过程，以促进 肿瘤生长该提案的总体目标是将肿瘤特异性代谢脆弱性靶向更多的肿瘤细胞。 有效地阻止IDH突变胶质瘤生长。这是基于初步数据，表明激活的 使用Sirt 1激活化合物（STAC）或Sirt 1过表达的关键代谢调节因子Sirt 1，导致 IDH突变细胞的细胞毒性，导致IDH突变胶质瘤对Sirt 1激活的敏感性是 与IDH诱导的代谢重组有关这个为期五年的职业发展项目旨在调查 使用原位小鼠研究IDH突变胶质瘤中Sirt 1激活的代谢基础和有效性 模型这项研究还将确定代谢靶向与抑制代谢靶向相结合的有效性。 细胞周期，一种基于靶向两个过程的前提的策略可以实现更有效的肿瘤治疗。 根除第一个目标将测试STAC与细胞周期抑制相结合的抗肿瘤效果 使用脑内植入的患者来源的IDH突变胶质瘤系。第二个目标是利用RNA- 测序以研究受STAC影响的细胞过程。第三个目标是探索 热量限制，已知通过Sirt 1上调发挥长寿促进作用，以增强细胞周期 抑制和防止胶质瘤生长。 米勒博士是一位训练有素、充满激情的医生兼科学家， 神经胶质瘤的治疗她是哈佛医学院帕帕斯中心的神经病学讲师， 马萨诸塞州总医院神经肿瘤科。此K 08应用程序旨在构建于以前的 癌症研究经验，以发展研究神经胶质瘤生物学的专业知识。她的导师卡希尔博士 Wakimoto等人是IDH突变胶质瘤代谢和建模领域的领导者。拟议项目将 还利用与单细胞转录组学和代谢领域的领先者的合作。这些专业知识 由候选人的科学顾问Brastianos博士和Batchelor博士补充，他们是 转化神经肿瘤学该奖项将进一步得到无与伦比的机构支持， 由马萨诸塞州总医院和哈佛医学院提供的环境。米勒博士未来的目标是 利用在此奖项期间获得的专业知识来研究新疗法对人类患者的影响， 胶质瘤K 08是建立神经肿瘤学转化研究计划的重要垫脚石 最终成为一名独立的R 01资助的调查员

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.