STM：Dovitinib对肾细胞癌可能有效性
6月6日，Sci. Transl. Med.报道了一种新的肾细胞癌（RCC）肿瘤移植模型，可用于临床前药效的评估。大多数进入临床试验的抗癌药没能获得美国FDA的最终认可。由于缺乏具有临床疗效预见性的临床前模型，药物研发进展缓慢。为此，研究者研发了一种肾脏细胞瘤（RCC）肿瘤移植模型，并将其应用于评估实验性药物Dovitinib。
来源于94名患者的肿瘤标本未经添加剂和解聚，直接移植于小鼠的肾脏。其中，35名患者的肿瘤标本形成了新的肿瘤，并建立了16个稳定的肿瘤系。从转移癌来源的肿瘤标本比从原发癌来源的移植成功率更高。而且，成功成瘤的原发癌标本往往来源于预后较差的患者。肿瘤移植物保留着其来源标本的组织型、基因表达、DNA拷贝数的变化以及大于90%的蛋白编码基因突变。对荷瘤小鼠高血钙诱导实验证实，肿瘤移植物还保留了诱导副癌综合征的能力。
应用RCC移植小鼠模型，研究者还比较了几种药物的药效，并证实了一种临床研发新药Dovitinib的有效性。这些实验表明，此类模型可在一定程度上反应人类肿瘤的分子遗传和药物敏感特点，为促进抗癌药物研发带来新的契机。
doi:10.1016/j.cell.2011.10.017
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A Validated Tumorgraft Model Reveals Activity of Dovitinib Against Renal Cell Carcinoma
Sharanya Sivanand1,2,3, Samuel Pe?a-Llopis1,2,3, Hong Zhao3, Blanka Kucejova1,2,3, Patrick Spence1,2,3, Andrea Pavia-Jimenez1,2,3, Toshinari Yamasaki1,2,3, David J. McBride4, Jessica Gillen1,2,3, Nicholas C. Wolff1,2,3, Lorraine Morlock5, Yair Lotan6, Ganesh V. Raj6, Arthur Sagalowsky6, Vitaly Margulis6, Jeffrey A. Cadeddu6, Mark T. Ross4, David R. Bentley4, Wareef Kabbani7, Xian-Jin Xie3, Payal Kapur7, Noelle S. Williams5 and James Brugarolas1,2,3,*
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. |
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