Imaging Biomarkers for Glioma Treatment Response

神经胶质瘤治疗反应的成像生物标志物

• 批准号: 10453751
• 负责人: Lawrence D Recht
• 金额: $ 21.68万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453751
• 关键词: Acetyl Coenzyme A; Aftercare; Analysis of Variance; Antineoplastic Agents; Area; Automobile Driving; Behavior; Bicarbonates; Biological Markers; Biomass; Bolus Infusion; Brain; Carbon Dioxide; Cell Proliferation; Clinic; Clinical; Clinical Research; Clinical Trials; Coenzyme Q10; Data; Deoxyglucose; Development; Energy Metabolism; Equilibrium; Follow-Up Studies; Glioma; Glucose; Glycolysis; Goals; Image; In Vitro; Injectable; Injections; Label; Lead; Lesion; Longterm Follow-up; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Glioma; Malignant Neoplasms; Measurement; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Morbidity - disease rate; Multivariate Analysis; Nodal; Normal tissue morphology; Outcome Measure; Oxidative Phosphorylation; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Pilot Projects; Positron-Emission Tomography; Predictive Value; Process; Production; Progression-Free Survivals; Pyruvate; Radiation therapy; Research; Resistance; Surrogate Markers; Suspensions; Testing; Therapeutic; Time; TimeLine; Tissues; Tumor Markers; Tumor Volume; Warburg Effect; anti-cancer; cancer cell; carbon skeleton; chemotherapeutic agent; clinical translation; conventional therapy; driving force; early phase clinical trial; first-in-human; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose metabolism; glucose uptake; image guided; image guided intervention; imaging biomarker; in vivo; in vivo Model; insight; metabolic imaging; multimodality; nano; novel; novel therapeutic intervention; outcome prediction; predicting response; preservation; primary outcome; refractory cancer; response; standard measure; synergism; temozolomide; treatment response; tumor; tumor metabolism; uptake

ABSTRACT Alteration of metabolism so as to favor a preponderance of glycolysis (GLY) relative to oxidative phosphorylation (OXPHOS) is considered a hallmark of cancer. Known originally as the Warburg effect, and now considered part of the larger concept of metabolic reprogramming, these cellular changes represent a way for cancer tissue to support rapid proliferation by preserving carbon skeletons for biomass production. Understanding the mechanisms that underlie this metabolic shift is an active area of research. In the context of therapeutics, insights from recent studies provide strong support that this reprogramming phenotype is necessary and sufficient to support the cancer process, thus providing a basis for highly novel therapeutic strategies in which either blocking or reversing metabolic reprogramming is the goal. Furthermore, malignant gliomas, highly glycolytic cancers exceedingly resistant to conventional treatments, seem particularly suited to approaches that can subvert this phenotype, and we believe the most crucial obstacle to moving such therapies to clinic has been the inability to reliably measure in vivo response to such metabolic therapies. The scientific premise of this proposal is that hyperpolarized 13C (HP13C) magnetic resonance imaging (MRI) offers great promise in fulfilling this clinical need. Pyruvate (Pyr), located at a crucial juncture in the brain glucose metabolic pathway where it can be either reduced to lactate (Lac) or converted to acetyl CoA + CO2, which is then converted to bicarbonate (Bic), has the potential to be used as a HP13C surrogate marker of the balance between GLY and OXPHOS. Following the bolus injection of HP [1-13C]Pyr, we propose that the observed 13C-Lac/13C-Bic (Lac/Bic) ratios can be used as a quantitative biomarker of a changing balance between these two metabolic processes, thus providing key information on glucose’s metabolic fate complementary to the uptake information provided by more commonly available 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET). Here, we propose to add simultaneous FDG-PET/HP13C/MRI measurements to an upcoming Phase II clinical trial of malignant glioma treated with BPM31510 (Berg LLC), a nano-suspension of Coenzyme Q10 showing high accumulation in cancer cell mitochondria and having marked antitumor activity in multiple in vivo models (both alone and in combination with chemotherapeutic agents) with in vitro evidence strongly suggesting the effect is mediated via increasing OXPHOS (i.e., reversing the Warburg effect). Our overall goal is to assess the potential synergy of combining information on glucose uptake, as provided by FDG-PET, and glucose metabolism, as provided by HP13C, for tumor characterization, assessment of therapeutic response, and prediction of patient outcome. If successful, the results from this pilot study would provide the critical preliminary data to justify larger follow-up studies of the use of these imaging biomarkers with anticancer metabolic therapies.

抽象的 改变新陈代谢，以有利于糖酵解（GLY）相对于氧化的优势 磷酸化（OXPHOS）被认为是癌症的标志。最初被称为瓦尔堡效应，并且 现在被认为是代谢重编程更大概念的一部分，这些细胞变化代表了一种方式 通过保留用于生物质生产的碳骨架来支持癌症组织的快速增殖。 了解这种代谢转变背后的机制是一个活跃的研究领域。在上下文中 就治疗学而言，最近研究的见解提供了强有力的支持，即这种重编程表型是 支持癌症过程所必需且充分的，从而为高度新颖的治疗提供基础 以阻断或逆转代谢重编程为目标的策略。此外，恶性 神经胶质瘤，一种高度糖酵解的癌症，对传统治疗极其耐药，似乎特别适合 可以颠覆这种表型的方法，我们认为移动这种表型的最关键障碍 临床疗法一直无法可靠地测量对此类代谢疗法的体内反应。 该提案的科学前提是超极化13C（HP13C）磁共振成像 （MRI）在满足这一临床需求方面提供了巨大的希望。丙酮酸（Pyr），位于大脑的关键节点 葡萄糖代谢途径，它可以被还原为乳酸 (Lac) 或转化为乙酰 CoA + CO2， 然后转化为碳酸氢盐 (Bic)，有潜力用作 HP13C 的替代标记 GLY 和 OXPHOS 之间的平衡。在推注 HP [1-13C]Pyr 后，我们建议 观察到的 13C-Lac/13C-Bic (Lac/Bic) 比率可用作平衡变化的定量生物标志物 这两个代谢过程之间的相互作用，从而提供有关葡萄糖代谢命运的关键信息 补充更常见的 18F-氟-脱氧-葡萄糖提供的摄取信息 正电子发射断层扫描（FDG-PET）。在这里，我们建议添加同步 FDG-PET/HP13C/MRI 对即将进行的用 BPM31510 (Berg LLC) 治疗的恶性神经胶质瘤的 II 期临床试验进行测量 辅酶 Q10 的纳米悬浮液在癌细胞线粒体中表现出高积累，并具有显着的效果 在多种体内模型（单独使用和与化疗药物联合使用）中具有抗肿瘤活性 体外证据强烈表明该效应是通过增加 OXPHOS 介导的（即逆转 瓦尔堡效应）。 我们的总体目标是评估结合所提供的葡萄糖摄取信息的潜在协同作用 FDG-PET 和 HP13C 提供的葡萄糖代谢，用于肿瘤表征、评估 治疗反应和患者结果的预测。如果成功的话，这项试点研究的结果将 提供关键的初步数据，以证明使用这些成像生物标志物的更大规模的后续研究是合理的 与抗癌代谢疗法。