Preclinical testing of an Atr inhibitor demonstrates improved response to standard therapies for esophageal cancer.
Preclinical testing of an Atr inhibitor demonstrates improved response to standard therapies for esophageal cancer.
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对ATR抑制剂的临床前测试表明，对食管癌的标准疗法的反应得到了改善。
DOI：
10.1016/j.radonc.2016.10.023
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发表时间：
2016-11
期刊：
影响因子：
--
通讯作者：
Hammond EM
中科院分区：
文献类型：
--
作者：
Leszczynska KB;Dobrynin G;Leslie RE;Ient J;Boumelha AJ;Senra JM;Hawkins MA;Maughan T;Mukherjee S;Hammond EM
食道癌的5年存活率一直很低，最近被英国癌症研究中心列为未得到满足的癌症。因此，迫切需要新的治疗方法。在这里，我们测试了ATR抑制剂VX-970与食道癌标准疗法联合使用可以改善治疗结果的假设。我们用食道癌细胞株评价了VX-970与顺铂、卡铂联合应用的效果，以及与放射治疗联合应用的效果。放射实验也在低氧条件下进行，以模拟肿瘤微环境。VX-970联合顺铂、卡铂和放射治疗可提高体外肿瘤细胞的杀伤率。VX-970联合放射治疗可明显延缓肿瘤生长。VX-970是一种有效的化疗/放射增敏剂，可以很容易地整合到当前的治疗范式中来提高食道癌的治疗效果，我们计划在即将到来的结合ATR抑制剂VX-970和食道癌放化疗的I阶段剂量递增安全性研究中对其进行前瞻性测试(EudraCT编号：2015-003965-27)。
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).
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影响因子：
16
作者：
Olcina, Monica M.;Foskolou, Iosifina P.;Anbalagan, Selvakumar;Senra, Joana M.;Pires, Isabel M.;Jiang, Yanyan;Ryan, Anderson J.;Hammond, Ester M.
通讯作者：
Hammond, Ester M.
影响因子：
12.3
作者：
Blasius M;Forment JV;Thakkar N;Wagner SA;Choudhary C;Jackson SP
通讯作者：
Jackson SP
DOI：
10.1158/1078-0432.ccr-15-0479
发表时间：
2015-11-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Karnitz LM;Zou L
通讯作者：
Zou L
影响因子：
30.8
作者：
Dulak, Austin M.;Stojanov, Petar;Peng, Shouyong;Lawrence, Michael S.;Fox, Cameron;Stewart, Chip;Bandla, Santhoshi;Imamura, Yu;Schumacher, Steven E.;Shefler, Erica;McKenna, Aaron;Carter, Scott L.;Cibulskis, Kristian;Sivachenko, Andrey;Saksena, Gordon;Voet, Douglas;Ramos, Alex H.;Auclair, Daniel;Thompson, Kristin;Sougnez, Carrie;Onofrio, Robert C.;Guiducci, Candace;Beroukhim, Rameen;Zhou, Zhongren;Lin, Lin;Lin, Jules;Reddy, Rishindra;Chang, Andrew;Landrenau, Rodney;Pennathur, Arjun;Ogino, Shuji;Luketich, James D.;Golub, Todd R.;Gabriel, Stacey B.;Lander, Eric S.;Beer, David G.;Godfrey, Tony E.;Getz, Gad;Bass, Adam J.
通讯作者：
Bass, Adam J.
影响因子：
14.8
作者：
Reaper, Philip M.;Griffiths, Matthew R.;Pollard, John R.
通讯作者：
Pollard, John R.