Potent antitumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal cancer patient-derived tumor explant model.

Autor: Song EK; Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Aurora, CO; Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea., Tai WM, Messersmith WA, Bagby S, Purkey A, Quackenbush KS, Pitts TM, Wang G, Blatchford P, Yahn R, Kaplan J, Tan AC, Atreya CE, Eckhardt G, Kelley RK, Venook A, Kwak EL, Ryan D, Arcaroli JJ
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2015 Apr 15; Vol. 136 (8), pp. 1967-75. Date of Electronic Publication: 2014 Sep 29.
DOI: 10.1002/ijc.29225
Abstrakt: Antiangiogenic therapy is commonly used for the treatment of colorectal cancer (CRC). Although patients derive some clinical benefit, treatment resistance inevitably occurs. The MET signaling pathway has been proposed to be a major contributor of resistance to antiangiogenic therapy. MET is upregulated in response to vascular endothelial growth factor pathway inhibition and plays an essential role in tumorigenesis and progression of tumors. In this study, we set out to determine the efficacy of cabozantinib in a preclinical CRC patient-derived tumor xenograft model. We demonstrate potent inhibitory effects on tumor growth in 80% of tumors treated. The greatest antitumor effects were observed in tumors that possess a mutation in the PIK3CA gene. The underlying antitumor mechanisms of cabozantinib consisted of inhibition of angiogenesis and Akt activation and significantly decreased expression of genes involved in the PI3K pathway. These findings support further evaluation of cabozantinib in patients with CRC. PIK3CA mutation as a predictive biomarker of sensitivity is intriguing and warrants further elucidation. A clinical trial of cabozantinib in refractory metastatic CRC is being activated.
(© 2014 UICC.)
Databáze: MEDLINE
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