Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts.
Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts.
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DOI：
10.1038/sj.bjc.6604995
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发表时间：
2009-04-21
影响因子：
8.8
通讯作者：
Hedley, D. W.
中科院分区：
文献类型：
--
作者：
Cao, P.;Maira, S-M;Garcia-Echeverria, C.;Hedley, D. W.
磷脂酰肌醇-3-激酶(PI3K)/Akt信号通路在胰腺癌中经常失控，被认为是胰腺癌生物学侵袭性和耐药性的重要决定因素。NVP-BEZ235是一种新型的双I类PI3K/哺乳动物雷帕霉素(MTOR)抑制剂靶点，正在进行I期人体临床试验。为了模拟临床试验，研究了NVP-BEZ235在5例早期传代的胰腺癌原位移植瘤中的作用。这些肿瘤显示PKB/Akt被激活，并且至少一种在胰腺癌中通常被激活的受体酪氨酸激酶的水平增加。在急性单次给药后测定药效学效应，在慢性药物暴露后在不同组测定抗癌作用。急性口服NVP-BEZ235可显著抑制PKB/Akt的磷酸化，并在24 h后恢复，对Ser235/236S6核糖体蛋白和Thr37/46 4E-BP1也有抑制作用，这与NVP-BEZ235作为PI3K/mTOR双重抑制剂的作用一致。NVP-BEZ235慢性给药45 mg kg−1耐受性良好，在3种模型中均有明显的肿瘤生长抑制作用。这些结果预测针对PI3K/Akt/mTOR通路的药物可能在胰腺癌患者中具有抗癌活性，并支持涉及化疗或其他分子靶向药物的联合研究的测试。
The phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway is frequently deregulated in pancreatic cancers, and is believed to be an important determinant of their biological aggression and drug resistance. NVP-BEZ235 is a novel, dual class I PI3K/mammalian target of rapamycin (mTor) inhibitor undergoing phase I human clinical trials. To simulate clinical testing, the effects of NVP-BEZ235 were studied in five early passage primary pancreatic cancer xenografts, grown orthotopically. These tumours showed activated PKB/Akt, and increased levels of at least one of the receptor tyrosine kinases that are commonly activated in pancreatic cancers. Pharmacodynamic effects were measured following acute single doses, and anticancer effects were determined in separate groups following chronic drug exposure. Acute oral dosing with NVP-BEZ235 strongly suppressed the phosphorylation of PKB/Akt, followed by recovery over 24 h. There was also inhibition of Ser235/236 S6 ribosomal protein and Thr37/46 4E-BP1, consistent with the effects of NVP-BEZ235 as a dual PI3K/mTor inhibitor. Chronic dosing with 45 mg kg−1 of NVP-BEZ235 was well tolerated, and produced significant tumour growth inhibition in three models. These results predict that agents targeting the PI3K/Akt/mTor pathway might have anticancer activity in pancreatic cancer patients, and support the testing of combination studies involving chemotherapy or other molecular targeted agents.
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