In May 2007, sorafenib was approved for “unresectable hepatocellular carcinoma (HCC), and was the first molecular targeted agent for use in liver cancer. Now many new agents are being developed and the combination therapy with sorafenib and standard treatment are being tried to conquer the liver cancer. The new agents includ mTOR inhibitors, Brivanib, Axitinib, E7080, CS1008 and many other agents.
Sorafenib is a multi-kinase inhibitor of tumor growth and angiogenesis, and exhibits a strong inhibitory effect on Cand B-Raf serine/threonine kinases, vascular endothelial growth factor receptor (VEGFR ) and platelet-derived growth factor receptor (PDGFR), tyrosine kinases, and FLT-3 and ckit.
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycine (mTOR) pathway also plays an important role in cell growth, survival regulation, metabolism and anti-apoptosis. Inhibiting mTOR with molecules, such as RAD001, generates additive effects that accompany upstream and downstream target inhibition; alternatively, upstream receptor inhibition is compensated for by inhibiting the downstream pathway, even if some resistance develops against receptor inhibition regardless of initial or acquired resistance. Therefore, RAD001 is a potential targeted agents for liver cancer.
The mTOR inhibitors includ everolimus (RAD001), sirolimus (Rapamune) and temsirolimus (CCI-779) and so on.
Brivanib is a kinase inhibitor that selectively inhibits VEGFR-1, -2 and -3, and FGFR-1, -2 and -3. So that the Angiogenesis can be inhibited, which is an important event not only for liver cancer but also for cancer growth and metastasis.
E7080 inhibits phosphorlation of growth factor receptors such as the VEGF receptor, KDR, Flt-1, FGFR1, and PDGFRβ-receptors that are important for angiogenesis. FGF and PDGF are potent promoters of tumor cellproliferation. With this action, E7080 is expected to exert its potent inhibition on tumor proliferation led by antiangiogenic effect with the inhibition of VEGF in addition to proliferation of tumor cells.
CS1008 is an agonistic agent to death receptor (DR) 5 or TNF-related apoptosis inducing ligand (TRAIL). In vitro nonclinical studies have shown that CS-1008 exhibits antitumor activity in DR5 positive tumor cells treated with CS-1008 and cross-linking with anti-human IgG antibody.CS-1008 was shown to induce apoptosis in DR5 positive tumor cells resulting in cell death.
Kudo M. Targeted therapy for liver cancer: updated review in 2012[J]. Current cancer drug targets, 2012, 12(9): 1062-1072.