Journal article
A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma
Science translational medicine, Vol.4(137), pp.137ra75-137ra75
06/06/2012
DOI: 10.1126/scitranslmed.3003643
PMCID: PMC3570965
PMID: 22674553
Abstract
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.
Details
- Title: Subtitle
- A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma
- Creators
- Sharanya Sivanand - Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USASamuel Peña-LlopisHong ZhaoBlanka KucejovaPatrick SpenceAndrea Pavia-JimenezToshinari YamasakiDavid J McBrideJessica GillenNicholas C WolffLorraine MorlockYair LotanGanesh V RajArthur SagalowskyVitaly MargulisJeffrey A CadedduMark T RossDavid R BentleyWareef KabbaniXian-Jin XiePayal KapurNoelle S WilliamsJames Brugarolas
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.4(137), pp.137ra75-137ra75
- DOI
- 10.1126/scitranslmed.3003643
- PMID
- 22674553
- PMCID
- PMC3570965
- NLM abbreviation
- Sci Transl Med
- ISSN
- 1946-6242
- eISSN
- 1946-6242
- Publisher
- United States
- Grant note
- R01 CA129387 / NCI NIH HHS R01CA129387 / NCI NIH HHS S10 RR025648 / NCRR NIH HHS U24CA126608 / NCI NIH HHS P30 CA142543 / NCI NIH HHS P01 CA095471 / NCI NIH HHS 1S10RR02564801 / NCRR NIH HHS 1P30CA142543 / NCI NIH HHS P01CA095471 / NCI NIH HHS U24 CA126608 / NCI NIH HHS
- Language
- English
- Date published
- 06/06/2012
- Academic Unit
- Preventive and Community Dentistry; Biostatistics; Dental Research
- Record Identifier
- 9983917664102771
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