Journal
RADIOTHERAPY AND ONCOLOGY
Volume 121, Issue 2, Pages 232-238Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.radonc.2016.10.023
Keywords
ATR; Esophageal cancer; Radiation; Hypoxia
Funding
- Medical Research Council UK [MC_PC_12001/2]
- NIHR Oxford Biomedical Research Centre
- CRUK grant
- CICAMS
- OCRC development fund
- Cancer Research UK [19276] Funding Source: researchfish
- Cancer Research UK
- Versus Arthritis [20874] Funding Source: researchfish
- Medical Research Council [MC_PC_12001/2] Funding Source: researchfish
- MRC [MC_PC_12001/2] Funding Source: UKRI
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Background and purpose: Esophageal cancer has a persistently low 5-year survival rate and has recently been classified as a cancer of unmet need by Cancer Research UK. Consequently, new approaches to therapy are urgently required. Here, we tested the hypothesis that an ATR inhibitor, VX-970, used in combination with standard therapies for esophageal cancer could improve treatment outcome. Material and methods: Using esophageal cancer cell lines we evaluated the efficacy of combining VX-970 with cisplatin and carboplatin in vitro and with radiation in vitro and in vivo. Radiation experiments were also carried out in hypoxic conditions to mimic the tumor microenvironment. Results: Combining VX-970 with cisplatin, carboplatin and radiation increased tumor cell kill in vitro. A significant tumor growth delay was observed when VX-970 was combined with radiotherapy in vivo. Conclusions: VX-970 is an effective chemo/radiosensitizer which could be readily integrated in the current treatment paradigm to improve the treatment response in esophageal cancer and we plan to test it prospectively in the forthcoming phase I dose escalation safety study combining the ATR inhibitor VX-970 with chemoradiotherapy in esophageal cancer (EudraCT number: 2015-003965-27). (C) 2016 The Authors. Published by Elsevier Ireland Ltd.
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