Dataset Information

Changes in Brain Energy and Membrane Metabolism in Glioblastoma following Chemoradiation.

ABSTRACT: Brain parenchyma infiltration with glioblastoma (GB) cannot be entirely visualized by conventional magnetic resonance imaging (MRI). The aim of this study was to investigate changes in the energy and membrane metabolism measured with phosphorous MR spectroscopy (31P-MRS) in the presumably "normal-appearing" brain following chemoradiation therapy (CRT) in GB patients in comparison to healthy controls. Twenty (seven female, thirteen male) GB patients underwent a 31P-MRS scan prior to surgery (baseline) and after three months of standard CRT (follow-up examination. The regions of interest "contrast-enhancing (CE) tumor" (if present), "adjacent to the (former) tumor", "ipsilateral distant" hemisphere, and "contralateral" hemisphere were compared, differentiating between patients with stable (SD) and progressive disease (PD). Metabolite ratios PCr/ATP, Pi/ATP, PCr/Pi, PME/PDE, PME/PCr, and PDE/ATP were investigated. In PD, energy and membrane metabolism in CE tumor areas have a tendency to "normalize" under therapy. In different "normal-appearing" brain areas of GB patients, the energy and membrane metabolism either "normalized" or were "disturbed", in comparison to baseline or controls. Differences were also detected between patients with SD and PD. 31P-MRS might contribute as an additional imaging biomarker for outcome measurement, which remains to be investigated in a larger cohort.

SUBMITTER: Grams AE

PROVIDER: S-EPMC8700426 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Changes in Brain Energy and Membrane Metabolism in Glioblastoma following Chemoradiation.

Grams Astrid Ellen AE Mangesius Stephanie S Steiger Ruth R Radovic Ivan I Rietzler Andreas A Walchhofer Lisa Maria LM Galijašević Malik M Mangesius Julian J Nowosielski Martha M Freyschlag Christian Franz CF Kerschbaumer Johannes J Gizewski Elke Ruth ER

Current oncology (Toronto, Ont.) 20211201 6

Brain parenchyma infiltration with glioblastoma (GB) cannot be entirely visualized by conventional magnetic resonance imaging (MRI). The aim of this study was to investigate changes in the energy and membrane metabolism measured with phosphorous MR spectroscopy (31P-MRS) in the presumably "normal-appearing" brain following chemoradiation therapy (CRT) in GB patients in comparison to healthy controls. Twenty (seven female, thirteen male) GB patients underwent a 31P-MRS scan prior to surgery (base ...[more]

PMID: 34940063

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Project description:Precise assessment of treatment response in glioblastoma during combined anti-angiogenic and chemoradiation remains a challenge. In particular, early detection of treatment response by standard anatomical imaging is confounded by pseudo-response or pseudo-progression. Metabolic changes may be more specific for tumor physiology and less confounded by changes in blood-brain barrier permeability. We hypothesize that metabolic changes probed by magnetic resonance spectroscopic imaging can stratify patient response early during combination therapy. We performed a prospective longitudinal imaging study in newly diagnosed glioblastoma patients enrolled in a phase II clinical trial of the pan-vascular endothelial growth factor receptor inhibitor cediranib in combination with standard fractionated radiation and temozolomide (chemoradiation). Forty patients were imaged weekly during therapy with an imaging protocol that included magnetic resonance spectroscopic imaging, perfusion magnetic resonance imaging, and anatomical magnetic resonance imaging. Data were analyzed using receiver operator characteristics, Cox proportional hazards model, and Kaplan-Meier survival plots. We observed that the ratio of total choline to healthy creatine after 1 month of treatment was significantly associated with overall survival, and provided as single parameter: (1) the largest area under curve (0.859) in receiver operator characteristics, (2) the highest hazard ratio (HR = 85.85, P = 0.006) in Cox proportional hazards model, (3) the largest separation (P = 0.004) in Kaplan-Meier survival plots. An inverse correlation was observed between total choline/healthy creatine and cerebral blood flow, but no significant relation to tumor volumetrics was identified. Our results suggest that in vivo metabolic biomarkers obtained by magnetic resonance spectroscopic imaging may be an early indicator of response to anti-angiogenic therapy combined with standard chemoradiation in newly diagnosed glioblastoma.

Project description:Introduction: Temozolomide (TMZ) is part of the standard of care for treating glioblastoma multiforme (GBM), an aggressive primary brain tumor. New approaches are needed to enhance therapeutic efficacy and reduce toxicity. GBM tumor cells are dependent on glucose and glutamine while relying heavily on aerobic fermentation for energy metabolism. Restricted availability of glucose and glutamine may therefore reduce disease progression. Calorically restricted ketogenic diets (KD-R), which reduce glucose and elevate ketone bodies, offer a promising alternative in targeting energy metabolism because cancer cells cannot effectively burn ketones due to defects in the number, structure, and function of mitochondria. Similarly, oxaloacetate, which participates in the deamination of glutamate, has the potential to reduce the negative effects of excess glutamate found in many brain tumors, while hyperbaric oxygen therapy can reverse the hypoxic phenotype of tumors and reduce growth. We hypothesize that the combinatorial therapy of KD-R, hyperbaric oxygen, and oxaloacetate, could reduce or eliminate the need for TMZ in GBM patients. Methods: Our proposed approach for inhibiting tumor metabolism involved various combinations of the KD-R, oxaloacetate (2 mg/g), hyperbaric oxygen, and TMZ (20 mg/kg). This combinatorial therapy was tested on adult VM/Dk mice bearing the VM-M3/Fluc preclinical GBM model grown orthotopically. After 14 days, tumor growth was quantified via bioluminescence. A survival study was performed and the data were analyzed and portrayed in a Kaplan Meier plot. Preliminary dosage studies were used and strict diet and drug administration was maintained throughout the study. Results: The therapeutic effect of all treatments was powerful when administered under KD-R. The most promising survival advantage was seen in the two groups receiving oxaloacetate without TMZ. The survival of mice receiving TMZ was diminished due to its apparent toxicity. Among all groups, those receiving TMZ had the most significant reduction in tumor growth. The most powerful therapeutic effect was evident with combinations of these therapies. Conclusion: This study provides evidence for a potentially novel therapeutic regimen of hyperbaric oxygen, oxaloacetate, and the KD-R for managing growth and progression of VM-M3/Fluc GBM.

Dataset Information

Changes in Brain Energy and Membrane Metabolism in Glioblastoma following Chemoradiation.

Publications

Changes in Brain Energy and Membrane Metabolism in Glioblastoma following Chemoradiation.

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