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

靶向 IDH 突变神经胶质瘤中的烟酰胺腺嘌呤二核苷酸 (NAD) 代谢

• 批准号: 10361197
• 负责人: Daniel P. Cahill
• 金额: $ 47.05万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10361197
• 关键词: Acute; Adult; Age; Antineoplastic Agents; Cancer Cell Growth; Cancer Control; Cancer Etiology; Cell Line; Cells; Cessation of life; Chemotherapy and/or radiation; Classification; Clinical; Coenzymes; Collaborations; Consumption; DNA Repair; DNA Sequence Alteration; Data; Dependence; Development; Diagnosis; Diagnostic; Diffuse; Disease; Dose; Dose-Limiting; Effectiveness; Enzymes; Etiology; Excision; Family; Gene Mutation; Genes; Genetic; Genotype; Glioma; Gliomagenesis; Glycolates; Goals; Hematology; Histologic; Homeostasis; Human; In Vitro; Investigation; Isocitrate Dehydrogenase; Lesion; Letters; Life; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Mediator of activation protein; Metabolic; Metabolism; Methods; Mission; Modeling; Modernization; Molecular; Monitor; Multienzyme Complexes; Mus; Mutation; Natural History; Nicotinamide adenine dinucleotide; Operative Surgical Procedures; Pathway interactions; Patients; Persons; Pharmacology; Phenotype; Poly(ADP-ribose) Polymerases; Predisposition; Proteins; Public Health; Publishing; Radiation; Recurrence; Research; Retina; SIRT1 gene; Signal Pathway; Sirtuins; Systemic Therapy; Testing; Therapeutic; Toxic effect; Translating; Work; World Health Organization; Xenograft Model; Xenograft procedure; cancer cell; chemotherapeutic agent; clinical translation; combinatorial; cytotoxicity; disorder control; driver mutation; efficacy evaluation; efficacy testing; enzyme biosynthesis; experimental study; improved; in vivo; in vivo Model; inhibitor; innovation; mutant; new therapeutic target; nicotinamide phosphoribosyltransferase; novel; overexpression; patient derived xenograft model; preclinical efficacy; small molecule; small molecule inhibitor; standard of care; stressor; systemic toxicity; temozolomide; therapeutic target; tumor; tumor growth; young adult

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.

弥漫性神经胶质瘤是45岁以下人群癌症相关死亡的主要原因 老年人，恶性脑肿瘤导致最大数量的潜在寿命损失， 美国成年人现代大规模遗传学发现已经确定了体细胞分子基因组 这些改变可以更好地对这些肿瘤进行分类。复发性异柠檬酸脱氢酶基因 在高达20%的成人弥漫性胶质瘤中发现了突变， 病因学、相关遗传变异和总体自然史。因此，IDH突变体 神经胶质瘤已被新确认为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在 20-50岁的年轻人，最初表现为低级别病变， 对标准护理治疗（如手术切除、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， 大多数情况下是致命的需要新的治疗方法。 在我们之前的工作中，我们已经表明IDH 1突变细胞内代谢的改变 暴露烟酰胺腺嘌呤二核苷酸（NAD+）生物合成酶烟酰胺 磷酸核糖基转移酶（NAMPT）的选择性抑制与小分子，导致 IDH 1突变癌细胞中的基因型特异性代谢脆弱性。突出 NAD+水平在IDH突变型胶质瘤中的重要性，这些观察结果强烈 表明靶向NAD+稳态的替代策略可以实现实质性的 对这些肿瘤的疗效。在此，我们建议评估NAD+稳态的调节， 通过多种非重叠方法在IDH突变型胶质瘤中检测IDH水平，以鉴定独特的 依赖性、敏感性介质和潜在的组合治疗策略。在 此外，我们计划测试创新的输送方法，以尽量减少毒性， 与NAMPTi单药治疗相关，拓宽了临床转化的治疗窗口。 我们提议的研究的成功完成将开辟新的途径， IDH 1突变胶质瘤独特的代谢脆弱性，转化为潜在的临床 治疗这些肿瘤的患者。

项目成果

PLK1 Inhibition Targets Myc-Activated Malignant Glioma Cells Irrespective of Mismatch Repair Deficiency-Mediated Acquired Resistance to Temozolomide.

• DOI: 10.1158/1535-7163.mct-18-0177
• 发表时间: 2018-12
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Higuchi F;Fink AL;Kiyokawa J;Miller JJ;Koerner MVA;Cahill DP;Wakimoto H
• 通讯作者: Wakimoto H

MGMT promoter methylation and hypermutant recurrence in IDH mutant lower-grade glioma.

IDH 突变低级别胶质瘤中的 MGMT 启动子甲基化和超突变复发。

• DOI: 10.1093/neuonc/noaa212
• 发表时间: 2020
• 期刊: Neuro-oncology
• 影响因子: 15.9
• 作者: Miller,JulieJ;Cahill,DanielP
• 通讯作者: Cahill,DanielP

Extent of Resection of Glioblastoma: A Critical Evaluation in the Molecular Era.

胶质母细胞瘤的切除程度：分子时代的关键评估。

• DOI: 10.1016/j.nec.2020.09.006
• 发表时间: 2021-01
• 期刊: Neurosurgery clinics of North America
• 影响因子: 2.6
• 作者: Cahill DP

Inductively coupled, transmit-receive coils for proton MRI and X-nucleus MRI/MRS in small animals.

用于小动物质子 MRI 和 X 核 MRI/MRS 的电感耦合发射-接收线圈。

• DOI: 10.1016/j.jmro.2023.100123
• 发表时间: 2023
• 期刊: Journal of magnetic resonance open
• 作者: Takahashi,AtsushiM;Sharma,Jitendra;Guarin,DavidO;Miller,Julie;Wakimoto,Hiroaki;Cahill,DanielP;Yen,Yi-Fen
• 通讯作者: Yen,Yi-Fen