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IDH1突变 继发性胶质母细胞瘤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。典型的胶质瘤相关IDH1突变编码突变的异柠檬酸脱氢酶 IDH1 R132H酶，获得将2-氧戊二酸(2-OG)转化为 代谢物R-2-羟基戊二酸(2-HG)。因此，2-HG在IDH1中累积到毫摩尔水平 突变型胶质瘤，是正常脑组织的100到1000倍。结构性的 2-HG和2-OG之间的相似性使2-HG能够竞争性地调节许多2-OG依赖的活性 双加氧酶，包括JmjC家族组蛋白去甲基酶、Tet家族DNA羟基酶和 低氧反应的脯氨酸羟基酶EGLN1。我们小组和其他人的研究证明了 表观遗传重连和HIF1α抑制在IDH1突变诱导的致癌程序中的作用 在神经胶质瘤中。尽管我们对IDH1 R132H癌蛋白的功能的了解已经扩大 非常成功地利用了正常和正常之间2-HG含量的内在差异 恶性脑组织改善临床疗效的研究尚未实现。我们的建议旨在解决 这在两个方面阻碍了进步。 首先，我们的目标是利用2-HG作为IDH突变状态的生物标志物，并优化方法学以 通过磁共振波谱(MRS)成像对这种代谢物进行非侵入性定量。我们 假设MRS生成的2HG浓度3D图可以用来补充传统的 T2/FLAIR成像能够更精确地描绘肿瘤边界，并在 手术切除的效率和胶质瘤患者治疗反应的量化。此外， 2HG 3DMRS成像是评估患者药效学反应的理想方法 参加正在进行的IDH靶向治疗的临床试验。 第二，我们的目标是开发新的治疗策略，旨在优先根除IDH1 通过靶向高2-HG积聚产生的脆弱性来突变胶质瘤细胞。药理作用 突变型IDH酶抑制剂在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，在IDH突变的胶质瘤中，这种抑制物的活性将大大降低。另一种选择 直接靶向突变IDH酶的方法需要利用IDH1-1的合成致死性 癌基因R132H。我们采用了正交假设驱动和基于筛选的方法来 确定NAD+代谢和从头合成嘧啶为IDH1突变型胶质瘤的靶向易损性 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。 IDH1突变型胶质瘤模型为这些新的治疗策略的临床研究奠定了理论基础。

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.