A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.
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.
Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Sharanya
S
Sivanand
Samuel
S
Peña-Llopis
Hong
H
Zhao
Blanka
B
Kucejova
Patrick
P
Spence
Andrea
A
Pavia-Jimenez
Toshinari
T
Yamasaki
David J
DJ
McBride
Jessica
J
Gillen
Nicholas C
NC
Wolff
Lorraine
L
Morlock
Yair
Y
Lotan
Ganesh V
GV
Raj
Arthur
A
Sagalowsky
Vitaly
V
Margulis
Jeffrey A
JA
Cadeddu
Mark T
MT
Ross
David R
DR
Bentley
Wareef
W
Kabbani
Xian-Jin
XJ
Xie
Payal
P
Kapur
Noelle S
NS
Williams
James
J
Brugarolas
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008875:Middle Aged; D015363:Quinolones / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D015363:Quinolones