Targeting metabolic vulnerabilities in Astrocytoma, IDH-mutant, Grade 4

项目总结 在2.6万例新诊断的脑和中枢神经系统恶性肿瘤中，神经胶质瘤占80% 肿瘤每年在美国发生，是最致命和最耐药的人类癌症之一。 尽管对于这种疾病迫切需要有效的治疗方法，但胶质瘤的标准治疗方法却没有。 自2005年以来发生了变化，在过去的十年里，没有新的药物疗法被批准用于成人胶质瘤。在……里面 作为对这一挑战的回应，我们设计了一种新的方法来治疗在这两个基因中任何一个发生突变的胶质瘤 IDH1或IDH2基因。总的来说，IDH突变存在于约20%的成人弥漫性胶质瘤中，这表明 这一患者群体的任何治疗进展都将产生广泛的影响。根据我们所知，IDH 突变会导致胶质瘤细胞深刻的代谢重新编程，我们使用了一种新的药理 筛选平台，以系统地识别此过程产生的漏洞。我们发现一个 一类针对核苷酸代谢的药物优先杀死具有IDH突变的胶质瘤细胞，从而 揭示了一种肿瘤选择性、生物标记物引导的治疗方法，有望在临床上快速转化。 为了在这一发现的基础上，并将对此漏洞的利用转化为临床，我们建议进行 IDH突变级别的脑穿透性核苷酸代谢抑制剂的0期手术窗临床试验 4例脑胶质瘤患者。我们将通过解决三个具体目标来描述对这一代理的反应。特定目标 第一种是使用基质辅助激光解吸电离质谱仪成像(MALDI-MSI)，传统的 液-质联用、核磁共振波谱等手段全面 胶质瘤靶向治疗药物的药代动力学和药效学特征 病人。具体目的#2是研究这种抑制物如何改变IDH突变的4级胶质瘤的生物学。 通过单细胞RNA测序分析原代组织标本的分子和细胞水平 和免疫组织化学。最后，具体目标3是评估这种药物的安全性和耐受性。 IDH突变型4级胶质瘤患者的焦点队列。综上所述，我们的工作将勾勒和测试一个新的 胶质瘤患者的治疗策略可以扩展到更大的多中心II期研究，如果我们的试验 是成功的。此外，我们努力阐明这一行动机制的关键组成部分 核苷酸代谢抑制剂有望为以联合治疗为中心的合理设计提供信息 可以在未来的研究中探索的这种制剂。

PROJECT SUMMARY Gliomas represent 80% of the 26,000 newly diagnosed cases of malignant brain and central nervous system tumors in the United States each year and are among the most lethal and treatment-resistant human cancers. Although there is a dire need for effective therapies for this disease, the standard treatment for gliomas has not changed since 2005 and no new medical therapies have been approved for adult gliomas in the last decade. In response to this challenge, we have devised a new way to treat gliomas that have a mutation in either of the IDH1 or IDH2 genes. Collectively, IDH mutations are present in ~20% of adult diffuse gliomas, indicating that any treatment advance in this patient population would have broad impact. Based on our knowledge that IDH mutations cause profound metabolic reprogramming in glioma cells, we used a novel pharmacological screening platform to systematically identify vulnerabilities that result from this process. We discovered that a class of drugs targeting nucleotide metabolism preferentially kill glioma cells with IDH mutations, thereby revealing an avenue for tumor-selective, biomarker-guided therapy that is poised for rapid clinical translation. To build on this discovery and translate exploitation of this vulnerability to the clinic, we propose to conduct a phase 0 surgical window clinical trial of a brain-penetrant nucleotide metabolism inhibitor in IDH-mutant grade 4 glioma patients. We will characterize response to this agent by addressing three Specific Aims. Specific Aim #1 is to use matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), conventional liquid chromatography-mass spectrometry, and magnetic resonance spectroscopy to comprehensively characterize the pharmacokinetic and pharmacodynamic properties of this targeted therapeutic in glioma patients. Specific Aim #2 is to investigate how this inhibitor alters the biology of IDH-mutant grade 4 gliomas at the molecular and cellular levels by analyzing resected primary tissue samples via single-cell RNA sequencing and immunohistochemistry. Finally, Specific Aim #3 is to evaluate the safety and tolerability of this drug in a focused cohort of IDH-mutant grade 4 glioma patients. Taken together, our work will outline and test a new treatment strategy for glioma patients that could be expanded to a larger multi-center phase II study if our trial is successful. Furthermore, our efforts to elucidate key components of the mechanism of action of this nucleotide metabolism inhibitor are expected to inform the rational design of combination therapies centered on this agent that can be explored in future studies.