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

项目总结： 摘要多形性胶质母细胞瘤是最常见的原发脑肿瘤，约 在美国，每年有8500例确诊病例。在15个月的时间内 尽管进行了治疗，但几乎所有的患者都死于这种有害的疾病。 因此，有必要采用新的、理想的肿瘤特异性方法来对抗这些疾病。 肿瘤。而单一试剂可能有效地靶向其他肿瘤，如血液学 恶性，胶质母细胞瘤有显著不同，因为它是一种肿瘤，其特点是 由于广泛的异质性，需要同时抑制理想的几个 放松管制的路径。我们之前的研究表明，靶向肿瘤 用于癌症治疗的线粒体具有显著的抗胶质瘤作用，特别是当 在联合疗法中使用。在这份提案中，一支经验丰富的调查团队 将通过引起肿瘤细胞来表征一种治疗胶质母细胞瘤的新概念 诱导IDH1突变的GBM合成致死性的特异性细胞死亡。在 首先，我们将剖析突变体IDH1和2-HG的最近端效应，涉及 肿瘤细胞代谢最终使肿瘤易受Bclxl抑制 介导的细胞凋亡。在第二个目标中，我们将测试是否干扰反 凋亡的Bcl-2家族成员与2-HG一起导致整合的应激反应 通过激活转录因子4(ATF4)介导的Noxa的增加，其中 TURN拮抗Mcl-1并启动肿瘤细胞的凋亡。在第三个目标中，我们将 评估IDH1突变是否对肿瘤线粒体具有合成致命性 靶向药物和延长与疾病相关的胶质瘤动物模型的动物存活时间。 总体而言，我们的研究可能有助于提供更具体和有效的治疗方法 患有基底膜的患者。总体而言，这项研究可能会增进我们对 关于脑瘤的治疗，并可能使我们有可能制定一种新的 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.