Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamide

Alessia Lodi; Renu Pandey; Jennifer Chiou; Ayon Bhattacharya; Shiliang Huang; Xingxin Pan; Brandon Burgman; S Stephen Yi; Stefano Tiziani; Andrew J Brenner

doi:10.3389/fonc.2022.900082

Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamide

Front Oncol. 2022 Sep 26:12:900082. doi: 10.3389/fonc.2022.900082. eCollection 2022.

Authors

Alessia Lodi^{1

2}, Renu Pandey^{1

2}, Jennifer Chiou^{1

2}, Ayon Bhattacharya³, Shiliang Huang³, Xingxin Pan⁴, Brandon Burgman^{4

5}, S Stephen Yi^{4

5

6

7}, Stefano Tiziani^{1

2

4

5

8}, Andrew J Brenner³

Affiliations

¹ Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, United States.
² Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, United States.
³ Mays Cancer Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
⁴ Department of Oncology, Dell Medical School, Livestrong Cancer Institutes, The University of Texas at Austin, Austin, TX, United States.
⁵ Institute for Cellular and Molecular Biology (ICMB), College of Natural Sciences, The University of Texas at Austin, Austin, TX, United States.
⁶ Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX, United States.
⁷ Oden Institute for Computational Engineering and Sciences (ICES), The University of Texas at Austin, Austin, TX, United States.
⁸ Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX, United States.

Abstract

Glioblastomas (GBM) are the most common and aggressive form of primary malignant brain tumor in the adult population, and, despite modern therapies, patients often develop recurrent disease, and the disease remains incurable with median survival below 2 years. Resistance to bevacizumab is driven by hypoxia in the tumor and evofosfamide is a hypoxia-activated prodrug, which we tested in a phase 2, dual center (University of Texas Health Science Center in San Antonio and Dana Farber Cancer Institute) clinical trial after bevacizumab failure. Tumor hypoxic volume was quantified by 18F-misonidazole PET. To identify circulating metabolic biomarkers of tumor hypoxia in patients, we used a high-resolution liquid chromatography-mass spectrometry-based approach to profile blood metabolites and their specific enantiomeric forms using untargeted approaches. Moreover, to evaluate early response to treatment, we characterized changes in circulating metabolite levels during treatment with combined bevacizumab and evofosfamide in recurrent GBM after bevacizumab failure. Gamma aminobutyric acid, and glutamic acid as well as its enantiomeric form D-glutamic acid all inversely correlated with tumor hypoxia. Intermediates of the serine synthesis pathway, which is known to be modulated by hypoxia, also correlated with tumor hypoxia (phosphoserine and serine). Moreover, following treatment, lactic acid was modulated by treatment, likely in response to a hypoxia mediated modulation of oxidative vs glycolytic metabolism. In summary, although our results require further validation in larger patients' cohorts, we have identified candidate metabolic biomarkers that could evaluate the extent of tumor hypoxia and predict the benefit of combined bevacizumab and evofosfamide treatment in GBM following bevacizumab failure.

Keywords: D-glutamic acid (D-Glu); bevacizumab (BEV); circulating metabolites; enantiomers; evofosfamide (TH-302); glioblastoma (GBM); metabolomics (OMICS).

Grants and funding

R35 GM133658/GM/NIGMS NIH HHS/United States