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岁以下患者与癌症相关死亡的主要原因 旧的，恶性脑肿瘤导致最大的潜在生命损失了 美国成年人。现代大规模遗传发现已经鉴定出体细胞分子基因组 可以更好地分类这些肿瘤的改变。复发性异位酸脱氢酶（IDH）基因 在多达20％的成人弥漫性神经胶质瘤中发现突变，鉴定出具有不同的肿瘤 病因，相关的遗传改变和整体自然历史。结果，IDH突变体 胶质瘤已被新认可为2016年世界内的独立诊断实体 卫生组织组织学分类。这些神经胶质瘤通常在 年轻的成年人从20至50岁不等，最初是较低的病变 对护理标准治疗的反应，例如手术切除，放射线和 化学疗法。但是，这些癌症无可避免地发展成为高级病变， 在大多数情况下证明是致命的。需要新的治疗方法。 在我们先前的工作中，我们表明了IDH1突变细胞内的新陈代谢改变 暴露烟酰胺腺嘌呤二核苷酸（NAD+）生物合成酶烟酰胺 磷酸贝糖基转移酶（NAMPT）以小分子的选择性抑制，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 NAD+水平在IDH突变胶质瘤中的核心重要性，这些观察结果强烈 建议针对NAD+稳态的替代策略可能实现大量 针对这些肿瘤的功效。在此，我们建议评估NAD+稳态的调制 通过多种非重叠方法，IDH突变胶质瘤的水平，以识别独特 依赖性，灵敏度介体和潜在的组合治疗策略。在 此外，我们计划测试可以最大程度地减少毒性的创新交付方法 与NAMPTI单一疗法相关，扩大了治疗窗口的临床翻译。 我们提出的研究的成功完成将为目标开放新的途径 IDH1突变胶质瘤的独特代谢脆弱性，转化为潜在的临床 这些肿瘤患者的疗法。

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.

• 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