Imaging Biomarkers for Glioma Treatment Response

摘要 代谢的改变，从而有利于糖酵解（GLY）相对于氧化糖酵解（GLY）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， 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， 通过保留碳骨架来生产生物质，使癌组织支持快速增殖。 了解这种代谢转变的机制是一个活跃的研究领域。背景下 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 必要和足够的支持癌症过程，从而为高度新颖的治疗方法提供基础。 以阻断或逆转代谢重编程为目标的策略。此外，恶性 神经胶质瘤是一种高度糖酵解的癌症，对常规治疗极有抵抗力，似乎特别适合于 可以颠覆这种表型的方法，我们相信， 将代谢疗法应用于临床的困难在于不能可靠地测量对这种代谢疗法的体内反应。 这项建议的科学前提是，超极化13 C（HP 13 C）磁共振成像 (MRI)为满足这一临床需求提供了巨大的希望。丙酮酸（Pyr），位于大脑的关键部位 葡萄糖代谢途径，其中它可以被还原为乳酸（Lac）或转化为乙酰辅酶A + CO2， 然后转化为碳酸氢盐（Bic），具有用作HP 13 C替代标记物的潜力。 GLY和OXPHOS之间的平衡。推注HP [1- 13 C]Pyr后，我们提出， 观察到的13 C-Lac/13 C-Bic（Lac/Bic）比值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联系，从而提供了关于葡萄糖代谢命运的关键信息 与更常见的18 F-氟脱氧葡萄糖提供的摄取信息互补 正电子发射断层扫描（FDG-PET）。在此，我们建议增加同步FDG-PET/HP 13 C/MRI 即将进行的用BPM 31510（贝格有限责任公司）治疗恶性胶质瘤的II期临床试验的测量， 辅酶Q10的纳米悬浮液显示在癌细胞线粒体中的高积累， 在多种体内模型（单独和与化疗剂组合）中的抗肿瘤活性， 体外证据强烈表明该作用是通过增加OXPHOS（即，扭转 瓦尔堡效应）。 我们的总体目标是评估结合葡萄糖摄取信息的潜在协同作用， FDG-PET和葡萄糖代谢，如HP 13 C所提供，用于肿瘤表征， 治疗反应和患者结果的预测。如果成功，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大型随访研究的合理性 抗癌代谢疗法。

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.