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|Ref Type||Journal Article|
|Authors||Fokas E, Prevo R, Pollard JR, Reaper PM, Charlton PA, Cornelissen B, Vallis KA, Hammond EM, Olcina MM, Gillies McKenna W, Muschel RJ, Brunner TB|
|Title||Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation.|
|Journal||Cell death & disease|
|Date||2012 Dec 06|
|Abstract Text||Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||pancreatic cancer||not applicable||Berzosertib + Gemcitabine + Radiotherapy||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Berzosertib (VX-970) enhanced the efficacy of radiotherapy combined with Gemzar (gemcitabine) in pancreatic cell line xenograft models, demonstrating a longer delay in tumor growth when compared to the models treated with only Gemzar (gemcitabine) and radiotherapy (PMID: 23222511).||23222511|
|Unknown unknown||pancreatic cancer||not applicable||Berzosertib + Radiotherapy||Preclinical - Cell line xenograft||Actionable||In a preclinical study, treatment with Berzosertib (VX-970) enhanced radiotherapy efficacy in pancreatic cells resulting in apoptotic induction in culture and DNA damage and tumor growth delay in cell line xenograft models (PMID: 23222511).||23222511|