6月6日，Sci. Transl. Med.報(bào)道了一種新的腎臟細(xì)胞瘤（RCC）腫瘤移植模型,，可用于臨床前藥效的評(píng)估。大多數(shù)進(jìn)入臨床試驗(yàn)的抗癌藥沒能獲得美國FDA的最終認(rèn)可,。由于缺乏具有臨床療效預(yù)見性的臨床前模型,，藥物研發(fā)進(jìn)展緩慢。為此,，研究者研發(fā)了一種腎臟細(xì)胞瘤（RCC）腫瘤移植模型,，并將其應(yīng)用于評(píng)估實(shí)驗(yàn)性藥物Dovitinib。
來源于94名患者的腫瘤標(biāo)本未經(jīng)添加劑和解聚,，直接移植于小鼠的腎臟,。其中，35名患者的腫瘤標(biāo)本形成了新的腫瘤,，并建立了16個(gè)穩(wěn)定的腫瘤系,。從轉(zhuǎn)移癌來源的腫瘤標(biāo)本比從原發(fā)癌來源的移植成功率更高。而且,，成功成瘤的原發(fā)癌標(biāo)本往往來源于預(yù)后較差的患者,。腫瘤移植物保留著其來源標(biāo)本的組織型、基因表達(dá),、DNA拷貝數(shù)的變化以及大于90%的蛋白編碼基因突變,。對(duì)荷瘤小鼠高血鈣誘導(dǎo)實(shí)驗(yàn)證實(shí)，腫瘤移植物還保留了誘導(dǎo)副癌綜合征的能力,。
應(yīng)用RCC移植小鼠模型,，研究者還比較了幾種藥物的藥效，并證實(shí)了一種臨床研發(fā)新藥Dovitinib的有效性,。這些實(shí)驗(yàn)表明,，此類模型可在一定程度上反應(yīng)人類腫瘤的分子遺傳和藥物敏感特點(diǎn)，為促進(jìn)抗癌藥物研發(fā)帶來新的契機(jī),。（生物谷bioon.com)
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.
