Potent antitumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal cancer patient-derived tumor explant model.
Potent antitumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal cancer patient-derived tumor explant model.
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DOI：
10.1002/ijc.29225
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发表时间：
2015-04-15
影响因子：
6.4
通讯作者：
Arcaroli, John J.
中科院分区：
文献类型：
--
作者：
Song, Eun-Kee;Tai, W. M.;Messersmith, Wells A.;Bagby, Stacey;Purkey, Alicia;Quackenbush, Kevin S.;Pitts, Todd M.;Wang, Guoliang;Blatchford, Patrick;Yahn, Rachel;Kaplan, Jeffrey;Tan, Aik Choon;Atreya, Chloe E.;Eckhardt, Gail;Kelley, Robin K.;Venook, Alan;Kwak, Eunice L.;Ryan, David;Arcaroli, John J.
抗血管生成疗法通常用于治疗CRC。尽管患者获得了一些临床益处，但治疗抵抗不可避免地发生。MET信号通路被认为是抗血管生成治疗耐药的主要原因。MET响应于VEGF通路抑制而上调，并且在肿瘤发生和肿瘤进展中起重要作用。在本研究中，我们着手确定卡博替尼在临床前CRC PDTX模型中的功效。我们在80%的治疗肿瘤中证明了对肿瘤生长的有效抑制作用。在具有PIK3CA基因突变的肿瘤中观察到最大的抗肿瘤作用。卡博替尼的潜在抗肿瘤机制包括抑制血管生成和Akt活化以及显著降低参与PI3K途径的基因的表达。这些发现支持在CRC患者中进一步评价卡博替尼。PIK3CA突变作为敏感性的预测生物标志物是有趣的，需要进一步阐明。卡博替尼在难治性转移性CRC中的临床试验正在启动。
Anti-angiogenic therapy is commonly used for the treatment of 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 anti-angiogenic therapy. MET is upregulated in response to VEGF 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 PDTX 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.
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影响因子：
11.5
作者：
Phay, John E.;Shah, Manisha H.
通讯作者：
Shah, Manisha H.
影响因子：
14.9
作者：
Kanehisa M;Araki M;Goto S;Hattori M;Hirakawa M;Itoh M;Katayama T;Kawashima S;Okuda S;Tokimatsu T;Yamanishi Y
通讯作者：
Yamanishi Y
影响因子：
28.2
作者：
Drilon A;Wang L;Hasanovic A;Suehara Y;Lipson D;Stephens P;Ross J;Miller V;Ginsberg M;Zakowski MF;Kris MG;Ladanyi M;Rizvi N
通讯作者：
Rizvi N
影响因子：
28.2
作者：
Bardelli A;Corso S;Bertotti A;Hobor S;Valtorta E;Siravegna G;Sartore-Bianchi A;Scala E;Cassingena A;Zecchin D;Apicella M;Migliardi G;Galimi F;Lauricella C;Zanon C;Perera T;Veronese S;Corti G;Amatu A;Gambacorta M;Diaz LA Jr;Sausen M;Velculescu VE;Comoglio P;Trusolino L;Di Nicolantonio F;Giordano S;Siena S
通讯作者：
Siena S
影响因子：
10.3
作者：
Graham, Timothy J.;Box, Gary;Robinson, Simon P.
通讯作者：
Robinson, Simon P.