Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer
Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer
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DOI：
10.1038/sj.bjc.6605819
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发表时间：
2010-08-24
影响因子：
8.8
通讯作者：
Hidalgo, M.
中科院分区：
文献类型：
--
作者：
Garrido-Laguna, I.;Tan, A. C.;Hidalgo, M.
背景：本研究的目的是确定在胰腺癌临床前模型中抑制哺乳动物雷帕霉素靶点（mTOR）的效果，并将临床前观察结果转化为临床。方法：将替西莫司（每天20 mg Kg(-1)）给予新生的胰腺癌异种移植物。28天后检测肿瘤生长抑制情况。异种移植物在基线时通过基因表达和比较基因组杂交进行表征。晚期吉西他滨耐药胰腺癌患者接受西罗莫司治疗（每日5mg）。主要终点为6个月生存率（6mSR）。相关研究包括基线肿瘤中通路表达的免疫组织化学评估、药物药代动力学（PKs）、FDG-PET反应评估和外周血单个核细胞（PBMCs）的药效学效应。结果：17例异种移植物中有4例（23%）对治疗有反应。敏感肿瘤的特征是基因拷贝数变异和导致PI3K/Akt/mTOR通路激活的基因过表达。在临床前研究中，p70S6K的激活与药物活性相关。西罗莫司在临床中耐受性良好，显示可预测的PKs，在治疗后pbmc中发挥通路抑制作用，导致6mSR为26%。然而，在肿瘤组织中激活的p70S6K与抗肿瘤作用之间没有发现相关性。结论：西罗莫司在胰腺癌中的活性是边缘性的，不能通过所选择的生物标志物来预测。英国癌症杂志（2010）103,649-655。doi: 10.1038 / sj.bjc。6605819 www.bjcancer.com 2010年7月27日(C) 2010年英国癌症研究中心
BACKGROUND: The purpose of this work was to determine the efficacy of inhibiting mammalian target of rapamycin (mTOR) in pancreatic cancer preclinical models and translate preclinical observations to the clinic.METHODS: Temsirolimus (20 mg Kg(-1) daily) was administered to freshly generated pancreatic cancer xenografts. Tumour growth inhibition was determined after 28 days. Xenografts were characterised at baseline by gene expression and comparative genomic hybridisation. Patients with advanced, gemcitabine-resistant pancreatic cancer were treated with sirolimus (5 mg daily). The primary end point was 6-month survival rate (6mSR). Correlative studies included immunohistochemistry assessment of pathway expression in baseline tumours, drug pharmacokinetics (PKs), response assessment by FDG-PET and pharmacodynamic effects in peripheral-blood mononuclear cells (PBMCs).RESULTS: In all, 4 of 17 xenografts (23%) responded to treatment. Sensitive tumours were characterised by gene copy number variations and overexpression of genes leading to activation of the PI3K/Akt/mTOR pathway. Activation of p70S6K correlated with drug activity in the preclinical studies. Sirolimus was well tolerated in the clinic, showed predictable PKs, exerted pathway inhibition in post-treatment PBMCs and resulted in a 6mSR of 26%. No correlation, however, was found between activated p70S6K in tumour tissues and anti-tumour effects.CONCLUSION: Sirolimus activity in pancreatic cancer was marginal and not predicted by the selected biomarker. British Journal of Cancer (2010) 103, 649-655. doi:10.1038/sj.bjc.6605819 www.bjcancer.com Published online 27 July 2010 (C) 2010 Cancer Research UK