Targeting metabolic vulnerabilities induced by the 1p19q codeletion in oligodendrogliomas

针对少突胶质细胞瘤中 1p19q 编码缺失引起的代谢脆弱性

• 批准号: 10722255
• 负责人: Pavithra Viswanath
• 金额: $ 18.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-25 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722255
• 关键词: 19q; 1p36; Adult; Anabolism; Astrocytes; Astrocytoma; Bioenergetics; Biological Assay; Biological Markers; Brain Neoplasms; Cancer Patient; Cells; Cessation of life; Chemotherapy and/or radiation; Chromosomes; Citric Acid Cycle; Classification; Clinic; Clinical; Cognitive; Cognitive deficits; Colon Carcinoma; Combined Modality Therapy; Companions; Compensation; Deuterium; Development; Drug Kinetics; Enzymes; Genes; Genomic medicine; Genomics; Glioma; Glucose; Glycolysis; Goals; Growth; Human; Image; Isocitrate Dehydrogenase; Label; Life; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Mass Spectrum Analysis; Metabolic; Metabolism; Modeling; Molecular; Molecular Genetics; Mus; Mutation; Neuroblastoma; Oncology; Outcome; Oxidation-Reduction; Patients; Phosphoenolpyruvate; Precision therapeutics; Primary Brain Neoplasms; Primates; Production; Proliferating; Protein Isoforms; Quality of life; Recurrence; Reporting; Safety; Specificity; Testing; Therapeutic; Translating; Translations; brain tissue; clinical translation; clinically relevant; enolase; genetic signature; glucose metabolism; imaging biomarker; imaging modality; improved outcome; in vivo; inhibitor; innovation; malignant breast neoplasm; metabolic imaging; metabolomics; mutant; non-invasive imaging; novel; novel therapeutics; oligodendroglioma; phosphoglycerate; precision medicine; pyruvate dehydrogenase; rational design; response; standard care; treatment response; tumor

PROJECT SUMMARY Gliomas are the most common malignant primary brain tumors in adults. Among gliomas driven by mutant isocitrate dehydrogenase, tumors harboring a 1p/19q codeletion are classified as oligodendrogliomas. Current therapies such as radiation and chemotherapy are highly toxic and cause long-lasting and life-altering deficits in cognitive and physical abilities. Importantly, although oligodendroglioma patients live for years with standard treatment, tumors inevitably recur and cause patient death. Since the 1p/19q codeletion is a hallmark of oligodendrogliomas, identifying metabolic vulnerabilities associated with the 1p/19 codeletion can lead to precision medicines for oligodendroglioma patients. Glycolytic metabolism, in particular, fuels biosynthesis and bioenergetics and is central to tumor proliferation. The glycolytic gene enolase 1, which is located on chromosome 1p36.23, is lost in oligodendrogliomas due to the 1p/19q codeletion, leaving these tumors dependent on enolase 2 (ENO2) for continued glycolysis. Our studies indicate that inhibiting ENO2 using a safe, potent ENO2 inhibitor (POMHEX) downregulates glycolysis in patient-derived oligodendrogliomas. However, ENO2 inhibition leads to a compensatory activation of pyruvate dehydrogenase (PDH), a key tricarboxylic acid (TCA) cycle enzyme. Importantly, combining POMHEX with the novel safe PDH inhibitor CPI- 613 completely abrogates glycolysis, the TCA cycle and oligodendroglioma growth. We will, therefore, test the hypothesis that targeting ENO2 and PDH is a precision therapy strategy for oligodendrogliomas (Aim 1). Successful translation of novel therapies is hindered by the lack of companion biomarkers that report on response to therapy. Magnetic resonance imaging, which is the mainstay of glioma imaging, fails to accurately report on response to therapy. Deuterium Magnetic Resonance Spectroscopy (DMRS) following administration of 2H-labeled substrates such as glucose is a safe clinically translatable method of imaging glycolytic flux in vivo. In Aim 2, we will examine the ability of 2H-glucose to report on response to ENO2 and PDH inhibition in oligodendrogliomas in vivo at clinically relevant field strength (3T). Our proposal is innovative and impactful because it will validate ENO2 and PDH as precision targets for oligodendrogliomas in this era of genomic medicine. Since the safety of POMHEX and CPI-613 has been established in primates and humans, and since DMRS can be readily deployed on clinical MR scanners, our therapies and companion biomarkers have the potential to be rapidly translated to the clinic. In essence, by simultaneously targeting metabolism for therapy and for imaging treatment response, our studies will enable precision medicine that improves outcomes and quality of life for oligodendroglioma patients.

项目摘要 胶质瘤是成人最常见的恶性原发性脑肿瘤。在由突变基因驱动的胶质瘤中， 异柠檬酸脱氢酶，携带1 p/19 q共缺失的肿瘤被分类为少突胶质细胞瘤。电流 放疗和化疗等治疗具有高毒性，会导致长期和改变生命的缺陷 在认知和身体能力方面。重要的是，尽管少突胶质细胞瘤患者在标准的 治疗时，肿瘤不可避免地复发并导致患者死亡。由于1 p/19 q共缺失是 少突胶质细胞瘤，识别与1 p/19共缺失相关的代谢脆弱性可导致 为少突胶质细胞瘤患者提供精准药物。糖酵解代谢，特别是燃料生物合成和 生物能量学和肿瘤增殖的核心。糖酵解基因烯醇化酶1位于 染色体1p36.23在少突胶质细胞瘤中由于1 p/19 q共缺失而丢失， 依赖烯醇化酶2（ENO 2）继续糖酵解。我们的研究表明，抑制ENO 2使用 安全有效的ENO 2抑制剂（POMHEX）下调患者来源的少突胶质细胞瘤中的糖酵解。 然而，ENO 2抑制导致丙酮酸脱氢酶（PDH）的代偿性激活，这是一个关键因素。 三羧酸（TCA）循环酶。重要的是，将POMHEX与新型安全的PDH抑制剂CPI- 613完全消除糖酵解、TCA循环和少突胶质细胞瘤生长。因此，我们将测试 假设靶向ENO 2和PDH是少突胶质细胞瘤的精确治疗策略（目的1）。 新疗法的成功转化受到缺乏报告以下方面的伴随生物标志物的阻碍： 对治疗反应。磁共振成像，这是神经胶质瘤成像的支柱，未能准确地 报告治疗反应。给药后的氘磁共振光谱（DMRS） 2 H标记底物如葡萄糖是一种安全的临床上可翻译的成像糖酵解通量的方法， vivo.在目的2中，我们将检查2 H-葡萄糖报告对EN 02和PDH抑制的响应的能力， 临床相关场强（3 T）下的体内少突胶质瘤。 我们的建议是创新和有影响力的，因为它将验证ENO 2和PDH作为精确目标， 少突胶质细胞瘤在这个基因组医学时代。由于POMHEX和CPI-613的安全性已被 在灵长类动物和人类中建立，并且由于DMRS可以很容易地部署在临床MR扫描仪上， 治疗和伴随生物标志物具有快速转化为临床的潜力。从本质上讲， 同时靶向代谢治疗和成像治疗反应，我们的研究将使 精准医疗，改善少突胶质细胞瘤患者的预后和生活质量。