Investigation of Sirt1 activation to target IDH mutant glioma

项目摘要 IDH突变型胶质瘤是一种无法治愈的原发性脑瘤，影响年轻人到中年人，是一种 由一个关键代谢基因的突变来定义。尽管接受了手术、放疗和化疗， 这些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突变的胶质瘤，重新编程代谢过程以促进 肿瘤生长。这项提案的首要目标是针对肿瘤特有的代谢脆弱性 有效抑制IDH突变型胶质瘤生长。这是基于初步数据表明， 关键代谢调节因子Sirt1，使用Sirt1激活化合物(STAC)或Sirt1过表达，导致 IDH突变细胞的细胞毒性，导致假设IDH突变胶质瘤对Sirt1激活的敏感性是 与IDH诱导的代谢重联有关。这个为期五年的职业发展项目旨在调查 原位小鼠IDH突变型胶质瘤的代谢基础和Sirt1激活效应 模特们。这项研究还将确定结合代谢靶向和抑制 细胞周期，一种基于这两个过程都可能实现更有效的肿瘤的前提的策略 根除。第一个目标是测试STAC结合细胞周期抑制的抗肿瘤效果。 使用患者来源的IDH突变胶质瘤细胞系植入大脑内。第二个目标是利用RNA-- 测序以研究STAC影响的细胞过程。第三个目标是探索 卡路里限制，已知通过上调Sirt1来发挥延长寿命的作用，以促进细胞周期 抑制和防止胶质瘤生长。 米勒博士是一位训练有素、充满激情的内科科学家，他独一无二地准备对 治疗神经胶质瘤。她是哈佛医学院帕帕斯中心的神经学讲师 马萨诸塞州综合医院的神经肿瘤学。此K08应用程序旨在基于以前的 癌症研究经验，以发展研究胶质瘤生物学的专业知识。她的导师卡希尔博士和 Wakimoto是IDH突变型胶质瘤代谢和建模领域的领导者。拟议的项目将 还要利用与单细胞转录学和新陈代谢领域公认的领导者的合作。这一专业知识 由候选人的科学顾问布拉斯蒂亚诺斯博士和巴切勒博士补充，他们是 翻译神经肿瘤学。这一奖项将得到无与伦比的机构支持和 麻省总医院和哈佛医学院提供的环境。米勒博士未来的目标是 利用在该奖项中获得的专业知识来研究新疗法对人类癌症患者的影响 神经胶质瘤。K08是建立神经肿瘤学翻译研究计划的重要垫脚石 最终成为一名独立的、由R01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.