Targeting Mutant IDH1 for a Novel Synthetic Lethal Interaction in Malignant Gliomas

项目概要： 多形性胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤， 美国每年确诊8500例。在15个月内 尽管进行了治疗，但实际上所有的患者都死于这种有害的疾病。 因此，新的，理想的肿瘤特异性方法是必要的，以打击这些 肿瘤的虽然单一试剂可以有效地靶向其他肿瘤，如血液肿瘤，但它可能是一种靶向肿瘤。 恶性肿瘤，胶质母细胞瘤是惊人的不同，因为它是一种肿瘤的特点是， 广泛的异质性，要求同时抑制理想的几个 解除管制的途径。我们之前的研究表明， 用于癌症治疗的线粒体引起显著的抗神经胶质瘤作用，特别是当 用于联合治疗。在这个提议中，一个有成就的调查小组 将描述一种新的胶质母细胞瘤治疗概念， 通过诱导IDH 1突变GBM中的合成致死性的特异性细胞死亡。在 第一个目标，我们将剖析突变IDH 1和2-HG的最近端效应，涉及 肿瘤细胞代谢，最终使肿瘤对Bcl-xL抑制敏感 介导的凋亡。在第二个目标中，我们将测试是否干扰反- 凋亡的Bcl-2家族成员沿着2-HG导致整合的应激反应 与转录激活因子4（ATF 4）介导的Noxa增加有关， turn拮抗Mcl-1并使肿瘤细胞凋亡。第三个目标，我们将 评估IDH 1突变是否对肿瘤线粒体具有合成致死性 靶向药物和延长神经胶质瘤疾病相关动物模型中的动物存活。 总的来说，我们的研究可能有助于提供更具体和有效的治疗方法， 患有GBM的患者。总的来说，这项研究可能会提高我们的理解， 关于脑肿瘤的治疗，并可能使我们能够制定一个新的 继发性胶质母细胞瘤和其他胶质瘤的治疗策略。

Project Summary: Glioblastoma multiforme (GBM) is the most common primary brain tumor with about 8500 cases diagnosed each year in the United States. Within a time frame of 15 month virtually all patients succumb to this detrimental disease despite treatment efforts. Therefore, novel, ideally tumor specific approaches are necessary to combat these tumors. While single reagents may efficiently target other tumors, such as hematological malignancies, Glioblastoma is strikingly different since it is a tumor that is characterized by extensive heterogeneity, demanding the simultaneous inhibition of ideally several deregulated pathways. Our previous research has shown that targeting tumor mitochondria for cancer therapy causes significant anti-glioma effects, especially when used in combination therapies. In this proposal, an accomplished team of investigators will be characterizing a novel treatment concept for glioblastoma by causing tumor-cell specific cell death through induction of synthetic lethality in IDH1 mutated GBMs. In the first aim, we will dissect the most proximal effect of mutant IDH1 and 2-HG, involving tumor cell metabolism that finally renders tumors susceptible to Bcl-xL inhibition mediated apoptosis. In the second aim, we will test as to whether interference with anti- apoptotic Bcl-2 family members along with 2-HG results in an integrated stress response with an Activating Transcription Factor 4 (ATF4) mediated increase of Noxa, which in turn antagonizes Mcl-1 and primes tumor cells to apoptosis. In the third aim, we will assess as to whether the IDH1 mutations are synthetically lethal with tumor mitochondria targeting drugs and extend animal survival in disease-relevant animal models of glioma. Overall, our research may help to provide more specific and efficient treatments for patients suffering from GBM. Overall, this research may enhance our understanding about the treatment of brain tumors and may potentially allow us to formulate a novel treatment strategy for secondary glioblastoma and other gliomas.