The Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins and the Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University, Baltimore, MD, USA.
Br J Cancer. 2010 Aug 24;103(5):649-55. doi: 10.1038/sj.bjc.6605819. Epub 2010 Jul 27.
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.
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).
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.
Sirolimus activity in pancreatic cancer was marginal and not predicted by the selected biomarker.
本研究旨在确定哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂在胰腺癌临床前模型中的疗效，并将临床前观察结果转化为临床实践。
给予新生成的胰腺癌异种移植物每天 20mg/kg 的替西罗莫司。28 天后测定肿瘤生长抑制情况。在基线时，通过基因表达和比较基因组杂交对异种移植物进行特征分析。对晚期、吉西他滨耐药的胰腺癌患者给予西罗莫司（每天 5mg）治疗。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 评估的反应和外周血单核细胞（PBMCs）中的药效学效应。
总共 17 个异种移植物中有 4 个（23%）对治疗有反应。敏感肿瘤的特点是基因拷贝数变异和导致 PI3K/Akt/mTOR 通路激活的基因过表达。p70S6K 的激活与临床前研究中的药物活性相关。西罗莫司在临床中耐受性良好，具有可预测的 PKs，在治疗后 PBMCs 中发挥通路抑制作用，6mSR 为 26%。然而，肿瘤组织中激活的 p70S6K 与抗肿瘤作用之间没有相关性。
西罗莫司在胰腺癌中的活性有限，所选生物标志物无法预测其疗效。
