title: Preclinical testing of an Atr inhibitor demonstrates improved response to standard therapies for esophageal cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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).
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, UK.
authors.forename: Katarzyna B
authors.initials: KB
authors.lastname: Leszczynska
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, UK.
authors.forename: Greg
authors.initials: G
authors.lastname: Dobrynin
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, UK.
authors.forename: Rhea E
authors.initials: RE
authors.lastname: Leslie
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ient
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, UK.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Boumelha
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, UK.
authors.forename: Joana M
authors.initials: JM
authors.lastname: Senra
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, UK.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Hawkins
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Maughan
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, UK.
authors.forename: Somnath
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, UK. Electronic address: Ester.Hammond@oncology.ox.ac.uk.
authors.forename: Ester M
authors.initials: EM
authors.lastname: Hammond
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage*; D051379:Mice; D011719:Pyrazines / Q000008:administration & dosage*
chemical_list: D007555:Isoxazoles; D011719:Pyrazines; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000598331:berzosertib
keywords: ATR; Esophageal cancer; Hypoxia; Radiation