Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Sci Transl Med. 2012 Jun 6;4(137):137ra75. doi: 10.1126/scitranslmed.3003643.
Most anticancer drugs entering clinical trials fail to achieve approval from the U.S. Food and Drug Administration. 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 kidneys of mice without additives or disaggregation. Tumors from 35 of these patients formed tumorgrafts, and 16 stable lines were established. Samples from metastatic sites engrafted at higher frequency than those from primary tumors, and stable engraftment of primary tumors in mice correlated with decreased patient survival. Tumorgrafts retained the histology, gene expression, DNA copy number alterations, and more than 90% of the protein-coding gene mutations of the corresponding tumors. As determined by the induction of hypercalcemia in tumorgraft-bearing mice, tumorgrafts retained the ability to induce paraneoplastic syndromes. In studies simulating drug exposures in patients, RCC tumorgraft growth was inhibited by sunitinib and sirolimus (the active metabolite of temsirolimus 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.
大多数进入临床试验的抗癌药物都未能获得美国食品和药物管理局的批准。药物开发受到缺乏具有治疗预测价值的临床前模型的阻碍。在此，我们报告了肾细胞癌 (RCC) 肿瘤植入模型的开发和验证及其在评估实验药物中的应用。从 94 名患者的肿瘤样本中，无需添加物或分散，直接植入到小鼠的肾脏中。其中 35 名患者的肿瘤形成了肿瘤植入物，建立了 16 个稳定的系。来自转移部位的样本比原发性肿瘤的样本更容易植入，并且原发性肿瘤在小鼠中的稳定植入与患者生存率的降低相关。肿瘤植入物保留了相应肿瘤的组织学、基因表达、DNA 拷贝数改变以及超过 90%的蛋白质编码基因突变。通过在携带肿瘤植入物的小鼠中诱导高钙血症来确定，肿瘤植入物保留了诱导副肿瘤综合征的能力。在模拟患者药物暴露的研究中，RCC 肿瘤植入物的生长被舒尼替尼和依维莫司（替西罗莫司在人类中的活性代谢物）抑制，但不受厄洛替尼抑制，厄洛替尼被用作对照。多韦替尼，一种处于临床开发阶段的药物，显示出比舒尼替尼和依维莫司更强的活性。将重现人类肿瘤分子遗传学和药物敏感性的模型常规纳入临床前计划，有可能改善肿瘤药物开发。
