In about two months, five days before Christmas, sorafenib will celebrate five years of approval by the FDA. When it was approved on December 20th, 2005, for advanced Renal Cell Carcinoma (RCC), it was the first (and is so far the only) approved drug to target B-Raf kinase, a signaling component of the MAPK pathway. Since then it has also been approved for Hepatocellular Carcinoma (HCC).
Sorafenib was discovered in a target-driven screen for Raf kinase inhibition in 1995 by Onyx-Bayer team. Sorafenib is a multikinase inhibitor (MKI). It inhibits VEGFR-1, -2 and -3, and PDGFR-ß, the key angiogenesis pathways driven by VEGF and PDGF. VEGF signaling is key for endothelial cell proliferation and neoangiogenesis, whereas, PDGF signaling in pericytes contribute to vessel stabilization and maturity. Raf/MEK/ERK pathway is downstream of VEGF and PDGF receptors. Sorafenib by targeting VEGFR2 in endothelial cells and PDGFR-ß in pericytes as well as inhibition of Raf kinase delivers a one-two-punch. Sorafenib also inhibits other tyrosine kinases such as c-KIT, RET and FLT-3 which is interesting because these, particularly c-KIT, are upregulated in many difficult to treat cancers. Thus, the drug may provide benefit in Phase 2 or 3 trials for other cancers.
(Figure from Nat Rev Drug Discov. 2006;5(10):835-844)
Advanced renal cell carcinoma patients today have at least six therapeutic options which appear to prolong survival. These include sorafenib tosylate (Nexavar, BAYER/ONYX), sunitinib malate (Sutent, PFIZER), temsirolimus (Torisol, WYETH), everolimus (Afinitor, NOVARTIS), bevacizumab (Avastin, GENENTECH/ROCHE) in combination with interferon, and pazopanib (Votrient, GSK).
"Sorafenib is a success story in many respects."
- No wonder, there are lawsuits to stop Cipla, who wants to get a piece of action, from claiming to invalidate Indian sorafenib patent no. 215758 (Bayer v. Cipla, Delhi High Court, April 18, 2010), and
- the survival data of sorafenib serves as a benchmark for upcoming RCC drugs, for example, AVEO Pharmaceuticals' Phase 2 study evaluating tivozanib.
NOTES:
Companies: Onyx Pharmaceuticals [NASDAQ:ONXX] and Bayer Healthcare are developing and marketing Nexavar under collaboration and co-promotion agreements.
PubMed: Preclinical premarketing data on sorafenib may also be under compound name "BAY 43-9006"
FURTHER READING:
- Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006;5(10):835-844. [PubMed] [GoogleScholar]
- Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125-134. [PubMed] [GoogleScholar]
- Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. [PubMed] [GoogleScholar]
- Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol. 2007;59(5):561-574 [PubMed]
- Finding the way in the jungle of kinase drug targets. Drug Discovery Today: Technologies. 2007;4(3-4):e91-e95. [GoogleScholar]
- New Therapeutic Strategies for Renal Cell Carcinoma. Urologic Nursing. 2010;30,(1):40-54. [Medscape]
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