Metabolic Therapy of GBM guided by MRS of hyperpolarized 13C-pyruvate

超极化13C-丙酮酸MRS引导的GBM代谢治疗

• 批准号: 9262926
• 负责人: Lawrence D Recht
• 金额: $ 54.85万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-09 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262926
• 关键词: Acetyl Coenzyme A; Acute; Address; Alanine; Angiogenesis Inhibitors; Avastin; Award; Awareness; Bicarbonates; Binding; Biological Markers; Biomass; Bolus Infusion; Brain Neoplasms; Carbon; Carbon Dioxide; Cells; Citric Acid Cycle; Clinic; Clinical; Clinical Markers; Clinical Trials; Collaborations; Data; Detection; Development; Dose; Ethylnitrosourea; Exposure to; Funding; Gap Junctions; Glioblastoma; Glioma; Glucose; Glutamates; Glycolysis; Goals; Growth; Hour; Image; Injectable; Injection of therapeutic agent; Investigation; Label; Laboratories; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Measurement; Measures; Metabolic; Metabolic Pathway; Metabolism; Methodology; Methods; Mitochondria; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Names; Neoplasms in Vascular Tissue; Nitrogen; Nodal; Noise; Nuclear; Nutrient; Oncogenes; Organism; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Paper; Pathway interactions; Permeability; Pharmaceutical Preparations; Physiologic pulse; Positron-Emission Tomography; Primary Brain Neoplasms; Process; Production; Pyruvate; Pyruvate Metabolism Pathway; Rattus; Refractory; Resistance; Resistance development; Resolution; Scientist; Signal Transduction; Surface; Survival Rate; Symbiosis; System; Techniques; Technology; Therapeutic; Time; Tissues; Translations; Transplantation; Treatment Efficacy; Tumor Angiogenesis; Vascular Endothelial Growth Factors; Warburg Effect; Work; aerobic glycolysis; angiogenesis; antitumor effect; base; bench to bedside; bevacizumab; cancer cell; carbon skeleton; cell killing; clinically relevant; computerized data processing; design; effectiveness measure; experimental study; improved; in utero; in vivo; interest; novel; public health relevance; pyruvate dehydrogenase; response; response biomarker; therapeutic biomarker; tool; treatment effect; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): In addition to their abnormally high proliferative rates, cancer cells universally demonstrate an abnormal metabolism that is characterized by an overutilization of glycolysis (GLY) relative to the more energy efficient mitochondrial oxidative phosphorylation (OXPHOS). Originally described over 80 years ago by Warburg, this altered metabolism, more recently termed metabolic reprogramming, is now viewed as a hallmark of cancer [1], and appears intimately tied to the proliferative state. The novel clinical implicationof these observations on tumor metabolism is that they suggest that a potential anticancer strategy lies in reverting this metabolism towards normal levels, i.e., forcing OXPHOS. Although this would not result in cell kill per se, it should result in stabilization of growth with minimal toxiity. However, although a number of targets exist for which active drugs can be directed, we contend that the major obstacle towards taking this to the clinic is the inability to measure cancer metabolism in the intact organism. The recent development of hyperpolarized 13C magnetic resonance spectroscopy (MRS) enables for the first time the real-time investigation of in vivo metabolism with more than a 10,000-fold signal increase over conventional 13C methods. Using 13C-labeled pyruvate (Pyr) as a substrate allows us to quantitatively follow the in vivo fate of pyruvate, which occupies a key nodal point in the metabolic pathway in which glucose is either converted to lactate (Lac; reflecting GLY) or acetyl CoA (generating bicarbonate [Bic] in the process; reflecting OXPHOS). With this technology, it is therefore possible to measure the 13C labeling of lactate and bicarbonate following the bolus injection of hyperpolarized [1-13C]-Pyr, thus permitting a Lac/Bic ratio to be calculated, which we propose to study as a marker of therapeutic response. Bevacizumab (BEV; Avastin®) is a monoclonal antibody (mab) that binds vascular endothelial growth factor (VEGF), thus inhibiting angiogenesis. It is widely used in a number of tumor types, including glioblastoma multiforme, the most malignant of the primary brain tumors. Although it can have dramatic initial effects, its duration tends to be relatively short-lived and associated with the development of refractory tumor progression. Although an intimate relationship between flow and metabolism is well documented, there has been little study of the impact of BEV on tumor metabolism. We have proposed that BEV acutely disrupts tumor metabolism at the tissue level, such as to force OXPHOS, and that this transient effect correlates with tumor stabilization [2]. By improving Bic detection to enable quantitation, we have observed a marked decrease in Lac/Bic ratio in transplanted glioblastoma tissue after anti-VEGF therapy, an effect that can be seen within three hours of administration, providing initial support for this counterintuitive hypothesis. Considering that despite extensive study into its antiangiogenic effects, neither a reliable early clinical marker of BEV effect nor o resistance development has been elucidated, our results offer a new and exciting direction for improving the impact of this very valuable oncotherapeutic. This project represents a collaboration between a group that has been on the cutting edge of this technology with the P.I., a clinician scientist who is familiar with clinical trials as well as laboratory models of brain cancer. Glioblastoma multiforme (GBM), the most commonly occurring primary brain tumor, is an excellent prototypical cancer with which to assess metabolic therapies because of its high rate of GLY and treatment refractoriness. However, it is important to note that the derived findings should apply to all cancer. Our experiments are designed in such a way that by the end of this funding period, we will have refined this technology so as to perform imaging with high resolution as well as to assess molecules such as glutamate which are "deeper" into the OXPHOS pathway (SA1), determine the time course and dose relationships of the BEV effect in transplanted glioblastoma (SA2), assess the impact of anti-VEGF therapy on "metabolic symbiosis" (SA3) and assess whether these findings extrapolate to a more clinically relevant model in which brain tumors develop "spontaneously" after exposure to a neurocarcinogen in utero (SA4). These experiments therefore should move us close to our ultimate goal of linking BEV's treatment impact with an optimal "lactate/bicarbonate ratio" that can be used clinically not only as a measure of therapeutic efficacy, but also as a therapeutic goal. The recent awarding of funds to purchase a clinical grade polarizer at Stanford should also us to accelerate the translation of findings from bench to bedside.

描述（由申请人提供）：除了其异常高的增殖率之外，癌细胞普遍表现出异常代谢，其特征在于相对于更节能的线粒体氧化磷酸化（OXPHOS）过度利用糖酵解（GLY）。这种改变的代谢，最近被称为代谢重编程，最初由瓦尔堡在80多年前描述，现在被视为癌症的标志[1]，并且似乎与增殖状态密切相关。 这些关于肿瘤代谢的观察结果的新的临床意义在于，它们表明潜在的抗癌策略在于将这种代谢恢复到正常水平，即，迫使OXPHOS。虽然这本身不会导致细胞杀伤，但它应该导致生长稳定，并具有最小的毒性。然而，尽管存在许多活性药物可以针对的靶点，但我们认为将其应用于临床的主要障碍是无法测量完整生物体中的癌症代谢。 超极化13 C磁共振波谱（MRS）的最新发展首次实现了对体内代谢的实时研究，其信号比传统13 C方法增加了10，000倍以上。使用13 C标记的丙酮酸（Pyr）作为底物，使我们能够定量跟踪丙酮酸的体内命运，丙酮酸占据代谢途径中的关键节点，其中葡萄糖转化为乳酸（Lac;反映GLY）或乙酰辅酶A（在此过程中产生碳酸氢盐[Bic];反映OXPHOS）。因此，使用这种技术，可以在超极化[1- 13 C]-Pyr的推注后测量乳酸盐和碳酸氢盐的13 C标记，从而允许计算Lac/Bic比率，我们建议将其作为治疗反应的标志物进行研究。 贝伐单抗（BEV; Avastin®）是一种单克隆抗体（mAb），可结合血管内皮生长因子（VEGF），从而抑制血管生成。它被广泛用于许多肿瘤类型，包括多形性胶质母细胞瘤，最恶性的原发性脑肿瘤。虽然它可以有显着的初始效果，其持续时间往往是相对短暂的，并与难治性肿瘤进展的发展。 虽然血流和代谢之间的密切关系是有据可查的，但关于BEV对肿瘤代谢的影响的研究很少。我们提出，BEV在组织水平上严重破坏肿瘤代谢，例如迫使OXPHOS，并且这种短暂效应与肿瘤稳定相关[2]。通过改进Bic检测以实现定量，我们已经观察到抗VEGF治疗后移植的胶质母细胞瘤组织中Lac/Bic比率显著降低，这种效果可以在给药后3小时内看到，为这种违反直觉的假设提供了初步支持。考虑到尽管对其抗血管生成作用进行了广泛的研究，但尚未阐明BEV效应的可靠早期临床标志物或耐药性发展，我们的结果为改善这种非常有价值的肿瘤治疗剂的影响提供了新的令人兴奋的方向。 这个项目代表了一个团队之间的合作，这个团队一直处于这项技术的前沿，一位熟悉临床试验和脑癌实验室模型的临床科学家。多形性胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，由于其高GLY发生率和治疗难治性，是评估代谢治疗的极好原型癌症。然而，重要的是要注意，得出的结果应适用于所有癌症。我们的实验是以这样一种方式设计的，即到本资助期结束时，我们将完善这项技术，以便进行高分辨率成像，并评估诸如谷氨酸等分子，这些分子“更深入”到OXPHOS途径（SA 1）中，确定BEV在移植的胶质母细胞瘤（SA 2）中的作用的时间过程和剂量关系，评估抗VEGF治疗对“代谢共生”的影响（SA 3），并评估这些发现是否外推到一个更具临床相关性的模型，其中脑肿瘤在子宫内暴露于神经致癌物后“自发”发展（SA 4）。 因此，这些实验应该使我们接近我们的最终目标，即将BEV的治疗效果与最佳的“乳酸盐/碳酸氢盐比例”联系起来，该比例不仅可以在临床上用作治疗效果的衡量标准，而且可以作为治疗目标。最近斯坦福大学拨款购买临床级偏光镜，也应该让我们加快将研究结果从实验室转化为临床应用。