subject: The Potent Action Of Regorafenib Against Angiogenesis [print this page] REGORAFENIB: EFFECT ON VEGFR REGORAFENIB: EFFECT ON VEGFR
The vital pathway which regulates the process of tumor angiogenesis is the VEGF pathway and is mediated through VEGF receptors like VEGFR-1, VEGFR-2, VEGFR-3. These receptors are the targets for various inhibitors which check the cancerous growth. Studies conducted with the renal cancer cells showed that VEGF signaling pathway is primarily deregulated during angiogenesis. This deregulation of the pathway is brought about by the loss of the VHL (von Hippel Lindau) protein. Use of Regorafenib inhibits the action of a large number of kinases in comparison to the inhibitors of the tyrosine kinases which are active against specific kinases only. Regorafenib shows an action against VEGFR and tyrosine kinases [1]. Various preclinical and clinical studies have shown that the process of angiogenesis is directly related with progression of melanoma. VEGFR is over expressed and the related VEGF protein is also produced in higher quantity. This stimulates the melanoma cell growth. Under in vitro conditions, the proliferation of melanoma cells involves an autocrine loop which is dependent on VEGF. An inhibitor which targets VEGF would not allow the formation of new blood vessels. This will cut the supply of oxygen and nutrients to the tumor cells. These inhibitors also show their impact on the different cell types present within the microenvironment of the tumor. These cells include endothelial cells, dendritic cells and progenitor cells of haematopoietic origin [2].
REGORAFENIB: AN INHIBITOR OF RTKS AND ANGIOGENESIS
The development of the tumor vasculature involves VEGFR2 and tyrosine kinases, which contain EGF homology domain 2 and immunoglobulin domain. Regorafenib is a newly detected inhibitor of multiple kinases which inhibit these endothelial kinases. These kinases were detected in various biochemical assays. Some additional kinases involved in the process of angiogenesis like VEGFR1/ VEGFR 3, FGF receptor1 and PDGF receptor- are also inhibited by Regorafenib. The kinases which have been subjected to mutation and have become oncogenic like RET, KIT, B-RAF, PDGFR are also inhibited by Regorafenib. MRI was done to study the antiangiogenic effect of this inhibitor. It was also tested on the vasculature of rats GS9L (xenograft model). The pouring out of Gadomer was significantly decreases when this inhibitor was administered at a concentration of 10 mg/kg. The microvessel area of the tumor was found to be significantly decreased in case of colorectal cancers. It showed a significant inhibition of the growth of tumors in a dose dependent manner. The breast cancer cell lines also showed shrinkage. This inhibitor is tolerated well under physiological conditions. Regorafenib targets not only the tumor but also the tumor vasculature. It has been found to be effective against solid tumors in phase II clinical trials [4].
CONCLUSION
In a nut shell Regorafenib is a newly discovered inhibitor of multiple kinases which show significant action against the process of angiogenesis.
REFERENCES
1. Bhargava P and Robinson MO. Development of Second-Generation VEGFR Tyrosine Kinase Inhibitors: Current Status. Curr Oncol Rep 2011 April; 13(2): 103111.
2. Corrie PG. Targeting angiogenesis in melanoma: prospects for the future. Ther Adv Med Oncol 2010 November; 2(6): 367380.
3. Wilhelm SM, Dumas J, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 2011 Jul 1; 129(1):245-55
4. Hedbom S, Steinbild S, et al. Phase I study of BAY 73-4506, a multikinase inhibitor, administered for 21 days on/7 days off in patients with advanced solid tumors. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings Part I 2007; 25(18S); 3593.
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