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.
While multiple novel therapeutic approaches aimed at reversing the abnormal metabolism driving rapid cellular proliferation in cancer are under active development, a major obstacle for robust clinical translation is our limited ability to noninvasively measure in vivo tumor metabolism and drug-induced changes thereof. Here we propose a pilot study to add new imaging biomarkers to an upcoming Phase II clinical trial of malignant glioma treated with a representative metabolic anticancer drug. This pilot study wll allow us to assess for the first time the synergistic potential of combining information from new magnetic resonance spectroscopic markers of glucose metabolism with conventional measurements of glucose uptake for assessing anticancer metabolic therapy response and predicting outcome.
