Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamide
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.900082/full |
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| author | Alessia Lodi Alessia Lodi Renu Pandey Renu Pandey Jennifer Chiou Jennifer Chiou Ayon Bhattacharya Shiliang Huang Xingxin Pan Brandon Burgman Brandon Burgman S. Stephen Yi S. Stephen Yi S. Stephen Yi S. Stephen Yi Stefano Tiziani Stefano Tiziani Stefano Tiziani Stefano Tiziani Stefano Tiziani Andrew J. Brenner |
| author_facet | Alessia Lodi Alessia Lodi Renu Pandey Renu Pandey Jennifer Chiou Jennifer Chiou Ayon Bhattacharya Shiliang Huang Xingxin Pan Brandon Burgman Brandon Burgman S. Stephen Yi S. Stephen Yi S. Stephen Yi S. Stephen Yi Stefano Tiziani Stefano Tiziani Stefano Tiziani Stefano Tiziani Stefano Tiziani Andrew J. Brenner |
| author_sort | Alessia Lodi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T07:28:21Z |
| format | Article |
| id | doaj.art-8d649ef526fa419aa6476b5269c3dcc0 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-14T07:28:21Z |
| publishDate | 2022-09-01 |
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| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-8d649ef526fa419aa6476b5269c3dcc02022-12-22T02:05:57ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-09-011210.3389/fonc.2022.900082900082Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamideAlessia Lodi0Alessia Lodi1Renu Pandey2Renu Pandey3Jennifer Chiou4Jennifer Chiou5Ayon Bhattacharya6Shiliang Huang7Xingxin Pan8Brandon Burgman9Brandon Burgman10S. Stephen Yi11S. Stephen Yi12S. Stephen Yi13S. Stephen Yi14Stefano Tiziani15Stefano Tiziani16Stefano Tiziani17Stefano Tiziani18Stefano Tiziani19Andrew J. Brenner20Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, United StatesDell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, United StatesDepartment of Nutritional Sciences, The University of Texas at Austin, Austin, TX, United StatesDell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, United StatesDepartment of Nutritional Sciences, The University of Texas at Austin, Austin, TX, United StatesDell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, United StatesMays Cancer Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United StatesMays Cancer Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United StatesDepartment of Oncology, Dell Medical School, Livestrong Cancer Institutes, The University of Texas at Austin, Austin, TX, United StatesDepartment of Oncology, Dell Medical School, Livestrong Cancer Institutes, The University of Texas at Austin, Austin, TX, United StatesInstitute for Cellular and Molecular Biology (ICMB), College of Natural Sciences, The University of Texas at Austin, Austin, TX, United StatesDepartment of Oncology, Dell Medical School, Livestrong Cancer Institutes, The University of Texas at Austin, Austin, TX, United StatesInstitute for Cellular and Molecular Biology (ICMB), College of Natural Sciences, The University of Texas at Austin, Austin, TX, United StatesDepartment of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX, United StatesOden Institute for Computational Engineering and Sciences (ICES), The University of Texas at Austin, Austin, TX, United StatesDepartment of Nutritional Sciences, The University of Texas at Austin, Austin, TX, United StatesDell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, United StatesDepartment of Oncology, Dell Medical School, Livestrong Cancer Institutes, The University of Texas at Austin, Austin, TX, United StatesInstitute for Cellular and Molecular Biology (ICMB), College of Natural Sciences, The University of Texas at Austin, Austin, TX, United StatesDepartment of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX, United StatesMays Cancer Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United StatesGlioblastomas (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.https://www.frontiersin.org/articles/10.3389/fonc.2022.900082/fullglioblastoma (GBM)bevacizumab (BEV)evofosfamide (TH-302)metabolomics (OMICS)circulating metabolitesenantiomers |
| spellingShingle | Alessia Lodi Alessia Lodi Renu Pandey Renu Pandey Jennifer Chiou Jennifer Chiou Ayon Bhattacharya Shiliang Huang Xingxin Pan Brandon Burgman Brandon Burgman S. Stephen Yi S. Stephen Yi S. Stephen Yi S. Stephen Yi Stefano Tiziani Stefano Tiziani Stefano Tiziani Stefano Tiziani Stefano Tiziani Andrew J. Brenner Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamide Frontiers in Oncology glioblastoma (GBM) bevacizumab (BEV) evofosfamide (TH-302) metabolomics (OMICS) circulating metabolites enantiomers |
| title | Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamide |
| title_full | Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamide |
| title_fullStr | Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamide |
| title_full_unstemmed | Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamide |
| title_short | Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamide |
| title_sort | circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab refractory glioblastoma after combined bevacizumab and evofosfamide |
| topic | glioblastoma (GBM) bevacizumab (BEV) evofosfamide (TH-302) metabolomics (OMICS) circulating metabolites enantiomers |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.900082/full |
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