Project 2 - Targeting IDH-mutant gliomas (Cahill/Kaelin)

在绝大多数低级别胶质瘤中发现复发热点IDH 1突变 和继发性胶质母细胞瘤已经彻底改变了我们对这些肿瘤的分子发病机制的理解， 恶性肿瘤。典型胶质瘤相关IDH 1突变编码突变型异柠檬酸脱氢酶 酶IDH 1 R132 H，其获得将2-酮戊二酸（2-OG）转化为 “癌代谢物”R-2-羟基戊二酸（2-HG）。因此，2-HG在IDH 1中积累至毫摩尔水平 突变型神经胶质瘤，相对于正常脑组织增加100至1000倍。结构性 2-HG和2-OG之间的相似性使得2-HG能够竞争性地调节许多2-OG依赖性细胞的活性。 双加氧酶，包括JmjC家族组蛋白去甲基化酶、泰特家族DNA羟化酶，以及 低氧反应脯氨酰羟化酶EglN 1。我们小组和其他人的研究表明， 表观遗传重布线和HIF 1 α抑制在IDH 1突变诱导的致癌程序中的作用 神经胶质瘤尽管我们对IDH 1 R132 H癌蛋白功能的理解已经扩展， 极大地，成功地利用了正常和正常之间2-HG含量的固有差异， 恶性脑组织以改善临床结果尚未实现。我们的建议旨在解决 这一障碍有两个方面。 首先，我们的目标是使用2-HG作为IDH突变状态的生物标志物，并优化方法学， 通过磁共振波谱（MRS）成像非侵入性地量化这种代谢物。我们 假设MRS生成的2 HG浓度的3D图可以用作传统的 T2/FLAIR成像能够更精确地描绘肿瘤边界，并改善肿瘤的生长。 手术切除的效率和胶质瘤患者治疗反应的量化。此外，委员会认为， 2 HG 3D MRS成像是评估患者药效学反应的理想方法 参加了正在进行的IDH靶向治疗的临床试验。 其次，我们的目标是开发新的治疗策略，旨在优先根除IDH 1 突变胶质瘤细胞通过靶向由高2-HG积累产生的脆弱性。药理 突变型IDH酶的抑制剂在IDH突变型白血病中显示出显著的活性，但早期临床 数据表明，这种抑制剂在IDH突变型神经胶质瘤中的活性显著降低。一个替代 直接靶向突变IDH酶的方法需要利用IDH 1- R132 H癌基因。我们采用了正交假设驱动和基于筛选的方法， 鉴定NAD+代谢和从头嘧啶合成作为IDH 1突变型胶质瘤的靶向弱点 细胞我们建议在临床前评估靶向这些代谢途径的安全性和有效性 IDH 1突变型胶质瘤的模型，建立这些新的治疗策略的临床研究的基本原理。

Discovery of a recurrent hotspot IDH1 mutation in the vast majority of low-grade gliomas and secondary glioblastomas has revolutionized our understanding of the molecular pathogenesis of these malignancies. The canonical glioma-associated IDH1 mutation encodes a mutant isocitrate dehydrogenase enzyme, IDH1 R132H, that gains the neomorphic ability to convert 2-oxoglutarate (2-OG) to the ‘oncometabolite’ R-2-hydroxyglutarate (2-HG). Consequently, 2-HG accumulates to millimolar levels in IDH1 mutant gliomas, representing a 100- to 1000-fold increase relative to normal brain tissue. The structural similarity between 2-HG and 2-OG enables 2-HG to competitively modulate the activity of many 2-OGdependent dioxygenases, including JmjC family histone demethylases, TET family DNA hydroxylases, and the hypoxia-responsive prolyl hydroxylase EglN1. Studies from our group and others demonstrate fundamental roles for epigenetic rewiring and HIF1alpha suppression in the oncogenic program induced by IDH1 mutations in glioma. Although our understanding of the function of the IDH1 R132H oncoprotein has expanded tremendously, successful exploitation of the inherent difference in 2-HG content between normal and malignant brain tissue to improve clinical outcomes has not yet been realized. Our proposal seeks to address this impediment to progress in two ways. First, we aim to use 2-HG as a biomarker of IDH mutational status and optimize methodology to quantify this metabolite non-invasively through magnetic resonance spectroscopy (MRS) imaging. We hypothesize that MRS-generated 3D maps of 2HG concentration could be used as a complement to traditional T2/FLAIR imaging to enable more precise delineation of tumor boundaries and yield improvements in the efficiency of surgical resection and the quantification of therapeutic responses in glioma patients. Furthermore, 2HG 3D MRS imaging represents an ideal approach to assess pharmacodynamic responses in patients enrolled in ongoing clinical trials of IDH targeting therapeutics. Second, we aim to develop novel therapeutic strategies designed to preferentially eradicate IDH1 mutant glioma cells by targeting vulnerabilities engendered by high 2-HG accumulation. Pharmacological inhibitors of mutant IDH enzymes have shown remarkable activity in IDH mutant leukemia but early clinical data suggest that such inhibitors will be considerably less active in IDH mutant gliomas. An alternative approach to directly targeting mutant IDH enzymes entails the exploitation of synthetic lethality with the IDH1- R132H oncogene. We have undertaken orthogonal hypothesis-driven and screening-based approaches to identify NAD+ metabolism and de novo pyrimidine synthesis as targetable vulnerabilities in IDH1 mutant glioma cells. We propose to evaluate the safety and efficacy of targeting these metabolic pathways in preclinical models of IDH1 mutant glioma to establish rationale for clinical studies of these novel therapeutic strategies.