Quantitation of nutrient metabolism in brain tumor patients using advanced 13C isotopomer technology

使用先进的 13C 同位素技术定量脑肿瘤患者的营养代谢

• 批准号: 10735720
• 负责人: Kumar Pichumani
• 金额: $ 36.41万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735720
• 关键词: Acetates; Acetyl Coenzyme A; Acetylcarnitine; Adjuvant Therapy; Affect; Bioenergetics; Biological; Brain; Brain Neoplasms; Cancer Patient; Carbon; Carbon Isotopes; Cell Line; Cell membrane; Citric Acid Cycle; Clinical Protocols; Clinical Trials; Complex; Data; Development; Diagnostic; Energy Metabolism; Energy-Generating Resources; Enrollment; Environment; Erythrocytes; Excision; Generations; Glioblastoma; Glioma; Glucose; Goals; Growth; Histologic; Hospitals; Human; Institutional Review Boards; Intervention; Intravenous infusion procedures; Isocitrate Dehydrogenase; Ketone Bodies; Knowledge; Label; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Malignant neoplasm of brain; Mass Spectrum Analysis; Metabolic; Metabolic Pathway; Metabolism; Metastatic malignant neoplasm to brain; Methodist Church; Methods; Mitochondria; Mutate; NMR Spectroscopy; Normal Cell; Nuclear Magnetic Resonance; Nutrient; Operative Surgical Procedures; Oral cavity; Outcome; Outcome Study; Patient Care; Patients; Phase I Clinical Trials; Physiological; Pilot Projects; Play; Preclinical Testing; Prediction of Response to Therapy; Primary Brain Neoplasms; Production; Proliferating; Property; Radioactivity; Resected; Slice; Solid Neoplasm; Source; Starvation; Technology; Testing; Therapeutic Intervention; Time; Tissue Sample; Tissues; Tumor Tissue; aggressive therapy; beta-Hydroxybutyrate; cancer cell; clinical development; clinically relevant; design; drug development; drug testing; first-in-human; imaging approach; improved; in vivo; in-vivo diagnostics; inhibitor; ketogenic diet; lipid biosynthesis; molecular imaging; mortality; neoplastic cell; new therapeutic target; novel; novel marker; novel therapeutic intervention; novel therapeutics; nutrient metabolism; overexpression; oxidation; pre-clinical; small molecule; small molecule inhibitor; spectroscopic imaging; targeted treatment; treatment planning; tumor; tumor diagnostic; tumor growth; tumor metabolism; tumor microenvironment

Project Summary/Abstract Malignant brain tumors are aggressive cancers that have high proliferative rates with much higher energy requirements and high mortality rates. Despite intense clinical and drug development efforts in the last two decades, there has been no improvement in survival. To support the abnormal growth commonly seen in tumors, the cancer cells have altered their metabolism compared to normal cells in healthy tissues. Most of the knowledge to date on cancer metabolism is derived from cultured cell lines. Probing metabolism in intact tumors will be critical to understand how the tumor cells grow in a patient under the complex biological tumor environment. From our pilot study involving a small number of patients, we have demonstrated that gliomas and brain metastases have the capacity to oxidize acetate in the citric acid cycle to meet their bioenergetic requirements, and glucose and acetate together contribute up to 63.0% of the total acetyl-CoA pool in these tumors. The remaining acetyl-CoA that provides carbon sources for biomolecular synthesis, must be derived from other nutrients. The following are the goals of this proposal: (1) determine if acetate and ketone body (beta hydroxybutyrate, BHB) utilization is a common property of all gliomas or specifically linked to high grade GBMs (2) examine whether acetate and BHB provide carbons for 2-hydroxyglutarate (2-HG) synthesis in IDH mutated glioma patients (3) preclinical testing of the effects of small molecule inhibitors of acetate and BHB, in freshly resected tumor tissue slices. We have Institutional Review Board (IRB) approved clinical protocol to infuse non-toxic and non-radioactive 13C-enriched acetate in patients who will be undergoing surgical removal of a brain tumor. Using Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry of these surgically resected tumor tissues, we will investigate the above described aims on energy metabolism of primary brain tumors. The attractiveness of this technology is that no radioactivity is involved. We anticipate that the outcome of this study will generate a detailed understanding of in vivo utilization of acetate and ketone body in brain tumor patients. This knowledge will lead to identification of key metabolic targets that may be further exploited for the development of new therapies. Additionally, it may identify novel biomarkers which may be helpful in designing non-invasive in vivo MRI methods to track acetate utilization by tumors for diagnostic purposes.

项目总结/摘要 恶性脑肿瘤是侵袭性癌症，具有高增殖率， 能源需求和高死亡率。尽管紧张的临床和药物开发 在过去二十年的努力中，生存率没有任何改善。支持 异常生长通常见于肿瘤，癌细胞已经改变了它们的新陈代谢 与健康组织中的正常细胞相比。迄今为止关于癌症代谢的大部分知识 来源于培养的细胞系。探索完整肿瘤的代谢对于理解 肿瘤细胞在复杂的肿瘤生物环境下如何在患者体内生长。从我们 在一项涉及少数患者的试点研究中，我们已经证明，胶质瘤和脑 转移瘤具有在柠檬酸循环中氧化乙酸盐的能力， 葡萄糖和乙酸盐共同贡献了总乙酰辅酶A的63.0%。 在这些肿瘤中。剩余的乙酰辅酶A为生物分子提供碳源， 合成，必须来自其他营养素。以下是本提案的目标：（1） 确定醋酸盐和酮体（β-羟基丁酸盐，BHB）的利用是否是常见的 所有胶质瘤的性质或与高级别GBM特异性相关（2）检查醋酸盐和 BHB为IDH突变的胶质瘤患者中的2-羟基戊二酸（2-HG）合成提供碳（3） 在新鲜切除的组织中， 肿瘤组织切片。我们有机构审查委员会（IRB）批准的临床方案， 在将要接受手术的患者中使用无毒和非放射性13 C富集醋酸盐 切除脑瘤使用核磁共振（NMR）光谱和质谱 为了研究这些手术切除的肿瘤组织的光谱，我们将研究上述 目的是研究原发性脑肿瘤的能量代谢。这项技术的吸引力在于， 不涉及放射性。我们预计，这项研究的结果将产生详细的 了解脑肿瘤患者体内醋酸盐和酮体的利用。这 知识将导致识别关键代谢目标，这些目标可以进一步用于 开发新的疗法。此外，它可以识别新的生物标志物，这可能是有帮助的。 在设计非侵入性体内MRI方法以跟踪肿瘤对乙酸盐的利用以进行诊断方面， 目的