A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.
A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.
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DOI：
10.1126/scitranslmed.3003643
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发表时间：
2012-06-06
影响因子：
17.1
通讯作者：
Brugarolas J
中科院分区：
文献类型：
--
作者：
Sivanand S;Peña-Llopis S;Zhao H;Kucejova B;Spence P;Pavia-Jimenez A;Yamasaki T;McBride DJ;Gillen J;Wolff NC;Morlock L;Lotan Y;Raj GV;Sagalowsky A;Margulis V;Cadeddu JA;Ross MT;Bentley DR;Kabbani W;Xie XJ;Kapur P;Williams NS;Brugarolas J
大多数进入临床试验的抗癌药物都没有获得美国食品药品监督管理局的批准。缺乏具有治疗预测价值的临床前模型阻碍了药物开发。在此，我们报告了肾细胞癌（RCC）肿瘤移植模型的建立和验证及其在实验性药物评估中的应用。来自94例患者的肿瘤样本被植入小鼠肾脏，没有添加任何添加剂或分解。35例患者肿瘤形成肿瘤移植物，16株稳定系建立。转移部位的样本移植频率高，小鼠原发肿瘤的稳定移植与患者生存率降低相关，这表明小鼠肿瘤的生长可能表明肿瘤获得了在远处生长和转移的能力。肿瘤移植物保留了相应肿瘤的组织学、基因表达、DNA拷贝数改变以及90%以上的蛋白质编码基因突变。通过对移植瘤小鼠高钙血症的诱导，肿瘤移植物能够作用于宿主，引起副肿瘤综合征。在模拟患者药物暴露的研究中，舒尼替尼和西罗莫司（替西莫司在人体内可转化为西罗莫司）抑制了RCC肿瘤移植物的生长，但作为对照的厄洛替尼没有抑制作用。Dovitinib，一种临床开发的药物，显示出比舒尼替尼和西罗莫司更大的活性。将人类肿瘤分子遗传学和药物敏感性的常规模型纳入临床前项目，有可能改善肿瘤药物的开发。
Most anticancer drugs entering clinical trials fail to achieve approval from the US FDA. Drug development is hampered by the lack of preclinical models with therapeutic predictive value. Herein, we report the development and validation of a tumorgraft model of renal cell carcinoma (RCC) and its application to the evaluation of an experimental drug. Tumor samples from 94 patients were implanted in the kidney of mice without additives or disaggregation. Tumors from 35 patients formed tumorgrafts, and 16 stable lines were established. Samples from metastatic sites engrafted at high frequency, and stable engraftment of primary tumors in mice correlated with decreased patient survival suggesting that tumor growth in mice may reveal the acquisition by the tumor of an ability to thrive at distant sites and metastasize. Tumorgrafts retained the histology, gene expression, DNA copy number alterations, and over 90% of the protein-coding gene mutations of the corresponding tumors. As determined by the induction of hypercalcemia in tumorgraft-bearing mice, tumorgrafts were able to act on the host causing paraneoplastic syndromes. In studies simulating drug exposures in patients, RCC tumorgraft growth was inhibited by sunitinib and sirolimus (into which temsirolimus is converted in humans), but not by erlotinib, which was used as a control. Dovitinib, a drug in clinical development, showed greater activity than sunitinib and sirolimus. The routine incorporation of models recapitulating the molecular genetics and drug sensitivities of human tumors into preclinical programs has the potential to improve oncology drug development.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Dondeti VR;Wubbenhorst B;Lal P;Gordan JD;D'Andrea K;Attiyeh EF;Simon MC;Nathanson KL
通讯作者：
Nathanson KL
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
6.2
作者：
Abou Youssif, Tamer;Fahmy, Mona Alam;Sircar, Kanishka
通讯作者：
Sircar, Kanishka
影响因子：
45.3
作者：
Atkins, MB;Hidalgo, M;Sherman, ML
通讯作者：
Sherman, ML