Regorafenib inhibits multiple kinases and controls the process of angiogenesis efficiently
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Posted On :
Dec-23-2011
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Article Word Count :
846
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A tumor needs a continuous blood supply for its growth beyond 1-2mm in dimension. The process of angiogenesis is related with the development of new blood vessels from the older ones and this process maintains a constant supply of oxygen to the growing tumor. The members belonging to the VEGF family promote the process of angiogenesis.
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A tumor needs a continuous blood supply for its growth beyond 1-2mm in dimension. The process of angiogenesis is related with the development of new blood vessels from the older ones and this process maintains a constant supply of oxygen to the growing tumor. The members belonging to the VEGF family promote the process of angiogenesis. Recent therapeutic approach targets this process within the malignant cells. Due to the insufficient supply of oxygen the malignant cells fail to sustain and die. Regorafenib is an efficient inhibitor of the process of angiogenesis.
ACTION OF REGORAFENIB ON ANGIOGENESIS
The members belonging to the VEGF family are the glycoproteins and they are stimulated by HIF-1? (transcription factor which creates a hypoxic microenvironment). Amongst the five members of VEGF family members VEGF-A is generally noticed at a higher level within the malignant tissues. VEGFR-1 and 2 are the two VEGF ligands which bind to the tyrosine kinase receptors situated on the membrane. Hence to control the growth of cancers the search began for a group of angiogenesis inhibitors. The MAPK and PI3K pathways are hyper-stimulated due to the over synthesis of VEGF and its related ligand (VEGFR). Under in vitro conditions an autocrine loop involving VEGF is activated. Anti- VEGF strategies have been highly useful to inhibit the growth of tumor within the xenograft models [1]. Cancer within the renal organ and the hepatic tissues is mainly controlled by a VEGF targeted therapy. Inhibitors which target the process of angiogenesis are broadly divided into two groups. One group of inhibitors inhibits the action of tyrosine kinases and the other is a set of monoclonal antibodies. Sorafenib belongs to the prior group of kinase inhibitors. It inhibits the action of VEGF ligands that is (VEGFR-2 and VEGFR-3). It worked well in combination with other chemotherapeutic agents like Taxol. Regorafenib proved to be highly potential in this line as it inhibited the action of both VEGFR-2 and Tie-2 receptor. The ligand angiopoietin binds to Tie-2 and stabilizes the blood vessel formation. Regorafenib inhibits the action of two different receptors and hence proves to be highly potent against angiogenesis [1].
REGORAFENIB AND RENAL CARCINOMA
Amidst the attempts to synthesize a second generation molecule which can inhibit VEGFR, there were few unsuccessful attempts also. For example – sunitinib was identified to be a selective inhibitor of VEGFR. But this did not produce positive results under in vitro conditions [1]. Renal carcinoma is thought to be efficiently controlled by checking the VEGF signaling pathway. Inhibitors like pazopanib and sorafenib target multiple kinases apart from VEGFR and hence they tend to stimulate many adverse effects [2]. Regorafenib is very selective in action and hence the adverse effects are also minimized.
PRECLINICAL STUDIES RELATED TO REGORAFENIB
Various preclinical studies have shown that Regorafenib not only inhibits VEGFR1 or VEGFR-3 but also certain other angiogenic kinases like PDGFR-?, FGFR 1 and mutated forms of BRAF, RET and KIT [3]. The pharmacodynamic and pharmacokinetic analysis shows that this inhibitor can be well tolerated at a concentration of 60 mg with no toxic side effects. It is also effective against pancreatic cancer [4].
CONCLUSION
In summary, Regorafenib inhibits multiple kinases and controls the process of angiogenesis efficiently. It controls the growth of large number of tumors by cutting the supply of oxygen.
REFERENCES
1. Corrie PG, Basu B and Ahmad Zaki K. Targeting angiogenesis in melanoma: prospects for the future. Ther Adv Med Oncol 2010; 2(6): 367-380.
2. Bhargava P and Robinson MO. Development of Second-Generation VEGFR Tyrosine Kinase Inhibitors: Current Status. Curr Oncol Rep 2011 April; 13(2): 103–111.
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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XL184, BEZ235, NVP-BEZ235,
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Health and Fitness
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Medicine
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