Targeting Nicotinamide Adenine Dinucleotide (NAD+) metabolism in IDH mutant gliomas

弥漫性胶质瘤是45岁以下人群癌症相关死亡的主要原因。 老年人，恶性脑瘤导致潜在寿命损失最多的年数 我们这些成年人。现代大规模基因发现确定了体细胞分子基因组 可以更好地对这些肿瘤进行分类的变化。复发异柠檬酸脱氢酶(IDH)基因 在高达20%的成人弥漫性胶质瘤中发现突变，这表明肿瘤具有明显的 病因学，相关的基因改变，以及整个自然历史。结果，IDH突变体 胶质瘤被新确认为2016年世界范围内的独立诊断实体 卫生组织组织学分类。这些神经胶质瘤通常被诊断为 20-50岁的年轻人，最初表现为较低级别的皮损，可以 对手术切除、放射治疗和 化疗。然而，这些癌症不可避免地发展成为更高级别的病变， 在大多数情况下被证明是致命的。需要新的治疗方法。 在我们之前的工作中，我们已经证明了IDH1突变细胞内代谢的变化 暴露烟酰胺腺嘌呤二核苷酸(NAD+)生物合成酶烟酰胺 磷酸核糖转移酶(NAMPT)用小分子选择性抑制，导致 IDH1突变癌细胞中深刻的基因型特异性代谢脆弱性。突出显示 IDH突变型胶质瘤中NAD+水平的中心重要性，这些观察结果很强 表明以NAD+动态平衡为目标的替代策略可能会取得实质性进展 对这些肿瘤的疗效。在此，我们建议评估NAD+稳态的调制 用多种非重叠方法检测IDH突变型胶质瘤中的水平，以确定唯一的 依赖性、敏感性的介体和潜在的联合治疗策略。在……里面 此外，我们计划测试创新的递送方法，以将毒性降至最低 与NAMPTi单一疗法相关联，拓宽了临床翻译的治疗窗口。 我们拟议的研究的成功完成将为目标定位开辟新的途径 IDH1突变型胶质瘤独特的代谢易感性，转化为潜在的临床 这些肿瘤患者的治疗方法。

Diffuse gliomas are a leading cause of cancer-related death in people under 45 years old, with malignant brain tumors resulting in the greatest number of years of potential life lost in US adults. Modern large-scale genetic discovery has identified somatic molecular genomic alterations that can better classify these tumors. Recurrent isocitrate dehydrogenase (IDH) gene mutations are found in up to 20% of adult diffuse gliomas, identifying tumors with distinct etiology, associated genetic alterations, and overall natural history. As a result, IDH mutant gliomas have been newly-recognized as separate diagnostic entities within the 2016 World Health Organization Histological Classification. These gliomas are typically diagnosed in younger adults ranging from 20-50 years old, initially presenting as lower-grade lesions that can be responsive to standard-of-care treatments such as surgical resection, radiation and chemotherapy. However, these cancers inexorably progress to become higher-grade lesions, and prove fatal in most cases. New treatments are needed. In our prior work, we have shown that the altered metabolism within IDH1 mutant cells exposes the nicotinamide adenine dinucleotide (NAD+) biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) to selective inhibition with small molecules, resulting in profound genotype-specific metabolic vulnerabilities in IDH1 mutant cancer cells. Highlighting the central importance of NAD+ levels in IDH mutant gliomas, these observations strongly suggest that alternative strategies targeting NAD+ homeostasis may achieve substantial efficacy against these tumors. Herein, we propose to evaluate modulation of NAD+ steady-state levels in IDH mutant gliomas by multiple non-overlapping approaches, to identify unique dependencies, mediators of sensitivity and potential combinatorial therapeutic strategies. In addition, we plan to test innovative delivery methods which could minimize the toxicities associated with NAMPTi monotherapy, widening the therapeutic window for clinical translation. The successful completion of our proposed research will open new avenues for targeting the unique metabolic vulnerabilities of IDH1 mutant gliomas, translating into potential clinical therapies for patients with these tumors.