In these patients, palliative treatment is possible, employing systemic therapy. Genetic profiling has suggested that HCC progression is attributed PF-6463922 to a number of altered signaling pathways as well as epigenetic mechanisms. Thus, as in other tumor entities,

targeted agents are investigated as novel therapeutic options. Along this line, angiogenesis inhibition is a prime therapeutic target in solid tumors, especially in highly vascularized HCC. Since the successful completion of the SHARP study in 2007,2 the antiproliferative and angiostatic multi–tyrosin kinase inhibitor (TKI), sorafenib, has been approved as the first systemic agent for treatment of patients with unresectable or metastatic HCC and preserved liver function. Sorafenib primarily inhibits BRAF/vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor tyrosin kinases mediating

cell proliferation and angiogenesis; it also blocks many additional kinases, given its lack of selectivity.3 The mechanism underlying the antitumor effect of sorafenib is complex, and even RAF-independent signaling has recently been described as a significant pathway of sorafenib-induced cell death.4 At present, sorafenib represents the only drug with statistically significant, but clinically modest, benefit in terms of improvement in overall survival (OS), time to Rapamycin order progression (TTP), and disease control rate. Efficacy of sorafenib in HCC was demonstrated in two

large randomized, controlled trials (RCT): SHARP and the Asia-Pacific study,2, 5 sorafenib significantly reduces the risk of death and prolongs median OS by approximately 3 months. Survival benefit is based on an extended TTP. Sorafenib does not induce tumor-size reduction, and radiologic response has to be confirmed by a decrease in viable tumor mass. Therefore, to identify novel drugs with activity in HCC in future and PAK5 ongoing trials, modified Response Evaluation Criteria In Solid Tumors criteria have been proposed.6 FGF3/4, fibroblast growth factors 3 and 4; FGFR, FGF receptor; HCC, hepatocellular carcinoma; OS, overall survival; RCT, randomized, controlled trial; TKI, multi–tyrosin kinase inhibitor; TTP, time to progression; VEGFR, vascular endothelial growth factor receptor. Sorafenib is associated with relevant toxicities, especially in patients with compromised liver function (stage Child-Pugh B). Patients with cirrhosis suffer from fatigue, and in such patients, sorafenib may cause a rapid deterioration in quality of life. Therefore, predictive (bio)markers to guide therapy with sorafenib are urgently needed. Many clinical parameters and serum markers as well as genomic signatures have been suggested; for example, development of hypertension and diarrhea, known side effects of sorafenib, under therapy seem to be associated with a favorable outcome.