Signaling Pathways

Nexavar is a multiple kinase inhibitor. It is both a RAF KINASE and VEGF-R/PDGFR inhibitor that, in pre-clinical studies, blocked tumor groth in two ways:

1. Inhibiting tumor cell proliferation
2. Inhibiting tumor angiogenises

• Signals from outside and inside the cell are sent to the nucleus through a process called signal transduction
• Nexavar is a targeted anti-cancer medicine that belongs to a new class of drugs called signal transduction inhibitors (STIs)
• The RAS protein is a key component of several signal transduction pathways involved in cellular proliferation, angiogenesis, and cellular death.
• RAS acts like a switch that transmits external signals through the signal pathway network, where signal transduction occurs. One well known pathway is the protein kinase cascade known as MAP Kinase Pathway
• The MAP kinase pathway consists of three kinases: RAF, MEK, and ERK, all which transmit membrane signals to the cell nucleus through a growth-regulating signal cascade
• In the nucleus, transcription factors are activated to regulate genes involved in growth and differentiation

Deregulation in the Pathways

• A common feature of cancer cells is deregulation in the signaling pathways. While normal cells are highly controlled, cancer cells continously transmit messages for cellular proliferation.
• This deregulation occurs through overexpression of growth factor receptors or through mutation in RAS and RAF
• In pre-clinical studies, Nexavar inhibited the activation of RAF kinase and thereby inhibited the activation of the RAF, MEK, ERK signaling pathway, a major contributor in uncontrolled cancer cell proliferation.
• Inhibiting cancer cell proliferation by blocking the sinaling pathway is the first of two ways Nexavar inhibited cancer growth in pre-clinical studies

Angiogenesis

• In pre-clinical studies, Nexavar also inhibited angiogenesis in blood vessels that feed vancer cells. In order to grow tumors must induce the growth of new blood vessels to provide themselves with nutrients and oxygen
• Angiogenesis begins with activation of blood vessels cell near the tumor by cell survival growth factors such as VEGF and PDGF
• This promotes blood vessels cell growth, migration, and tube formation

Anti-Angiogenesis

• Pre-clinical studies showed that Nexavar delivered multiple kinase inhibition to block tumor cell proliferation and angiogenesis in tumors, expanding the attack against advanced renal cell carcinoma