Glutaminase inhibition with telaglenastat (CB-839) improves treatment response in combination with ionizing radiation in head and neck squamous cell carcinoma models
| Autor: | Brian G. Hunt, Susan E. Waltz, Sunil Krishnan, Trisha Wise-Draper, Vinita Takiar, Kathryn E. Aziz, Christina A. Wicker, Gordon B. Mills, Shobha Parajuli, Sarah Palackdharry, William R. Elaban |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Treatment response Cell Survival Benzeneacetamides Article Ionizing radiation 03 medical and health sciences Mice 0302 clinical medicine Oxygen Consumption Radioresistance Cell Line Tumor Gene expression Thiadiazoles medicine Animals Humans Radiosensitivity Enzyme Inhibitors Cell Proliferation business.industry Glutaminase Squamous Cell Carcinoma of Head and Neck Head and neck cancer Chemoradiotherapy medicine.disease Head and neck squamous-cell carcinoma Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic stomatognathic diseases 030104 developmental biology Oncology Head and Neck Neoplasms 030220 oncology & carcinogenesis Cancer research Female business |
| Zdroj: | Cancer Lett |
| ISSN: | 1872-7980 |
| Popis: | The efficacy of ionizing radiation (IR) for head and neck cancer squamous cell carcinoma (HNSCC) is limited by poorly understood mechanisms of adaptive radioresistance. Elevated glutaminase gene expression is linked to significantly reduced survival (p < 0.03). The glutaminase inhibitor, telaglenastat (CB-839), has been tested in Phase I/II cancer trials and is well tolerated by patients. This study investigated if telaglenastat enhances the cellular response to IR in HNSCC models. Using three human HNSCC cell lines and two xenograft mouse models, we examined telaglenastat’s effects on radiation sensitivity. IR and telaglenastat combinatorial treatment reduced cell survival (p ≤ 0.05), spheroid size (p ≤ 0.0001) and tumor growth in CAL-27 xenograft bearing mice relative to vehicle (p ≤ 0.01), telaglenastat (p ≤ 0.05) or IR (p ≤ 0.01) monotherapy. Telaglenastat significantly reduced the Oxygen Consumption Rate/Extracellular Acidification Rate ratio in CAL-27 and HN5 cells in the presence of glucose and glutamine (p ≤ 0.0001). Telaglenastat increased oxidative stress and DNA damage in irradiated CAL-27 cells. These data suggest that combination treatment with IR and telaglenastat leads to an enhanced anti-tumor response. This pre-clinical data, combined with the established safety of telaglenastat justifies further investigation for the combination in HNSCC patients. |
| Databáze: | OpenAIRE |
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