Regorafenib inhibits growth, angiogenesis and metastasis in a highly aggressive, orthotopic colon cancer model
Menée à l'aide d'un modèle murin de cancer du côlon, cette étude évalue les effets du regorafenib sur la croissance tumorale, l'angiogenèse et le processus métastatique
The combination of target-specific drugs like bevacizumab with chemotherapeutics has improved treatment efficacy in advanced colorectal cancer (CRC). However, the clinical prognosis of metastatic CRC is still poor and novel drugs are currently assessed with respect to their efficacies in CRC patients. In a phase III study, the multi-kinase inhibitor regorafenib (BAY 73-4506) has recently been shown to prolong survival of CRC patients after standard therapies failed. In the present study, the activity of regorafenib was investigated in comparison with the angiogenesis inhibitor DC101 in the highly aggressive, murine CT26 metastatic colon cancer model. Whereas a treatment for 10 days with DC101 given at a dose of 34 mg/kg every third day significantly delayed tumor growth compared to vehicle-treated animals, regorafenib completely suppressed tumor growth at a daily oral dose of 30 mg/kg. Regorafenib also induced a stronger reduction in tumor vascularization, as longitudinally assessed in vivo by dynamic contrasted enhanced magnetic resonance imaging (DCE-MRI) and confirmed by immunohistochemistry. In addition, regorafenib inhibited the angiogenic activity more strongly and induced a three times higher apoptosis rate compared with DC101. Even more important, regorafenib completely prevented the formation of liver metastases, whereas in DC101-treated animals, the metastatic rate was only reduced by 33% compared to the vehicle group. Additionally, regorafenib significantly reduced the amount of infiltrating macrophages. These data demonstrate that the multi-kinase inhibitor regorafenib exerts strong anti-angiogenic, anti-tumorigenic and even anti-metastatic effects on highly aggressive colon carcinomas indicative for its high potential in the treatment of advanced CRC.
http://mct.aacrjournals.org/content/early/2013/04/25/1535-7163.MCT-12-1162.abstract