Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer, accounting for 90% of primary liver cancers. In the last decade it has become one of the most frequently occurring tumors worldwide and is also considered to be the most lethal of the cancer systems, accounting for approximately one third of all malignancies. Although the clinical diagnosis and management of early-stage HCC has improved significantly, HCC prognosis is still extremely poor. Furthermore, advanced HCC is a highly aggressive tumor with a poor or no response to common therapies. Therefore, new effective and well-tolerated therapy strategies are urgently needed. Targeted therapies have entered the field of anti-neoplastic treatment and are being used on their own or in combination with conventional chemotherapy drugs. Molecular-targeted therapy holds great promise in the treatment of HCC. A new therapeutic opportunity for advanced HCC is the use of sorafenib (Nexavar). On the basis of the recent large randomized phase III study, the Sorafenib HCC Assessment Randomized Protocol (SHARP), sorafenib has been approved by the FDA for the treatment of advanced HCC. Sorafenib showed to be able to significantly increase survival in patients with advanced HCC, establishing a new standard of care. Despite this promising breakthrough, patients with HCC still have a dismal prognosis, as it is currently the major cause of death in cirrhotic patients. Nevertheless, the successful results of the SHARP trial underscore the need for a comprehensive understanding of the molecular pathogenesis of this devastating disease. In this review we summarize the most important studies on the signaling pathways implicated in the pathogenesis of HCC, as well as the newest emerging drugs and their potential use in HCC management.
Highlights
Hepatocellular carcinoma (HCC) is the most common liver cancer, accounting for 90% of primary liver cancers
Positive p-RPS6 staining correlated with HCC recurrence after resection [94]. These data support efforts to target mammalian target of rapamycin (mTOR) signaling in liver cancer patients. These data suggest that the PI3K/ PTEN/Akt/mTOR pathway may represent an important therapeutic target for HCC treatment in patients with differing etiologies that lead to the development of this aggressive tumor
HCC occurring in HCV patients showed a high incidence of β-catenin gene mutations [109, 113], whereas in HCC occurring in HBV patients β-catenin activation is induced in a mutation-independent manner by the expression of HBx protein [114, 115]
Summary
Hepatocellular carcinoma (HCC) is the most common liver cancer, accounting for 90% of primary liver cancers. Recent discoveries in the complex networks involved in HCC proliferation, progression and survival have created many opportunities for targeted drugs and new therapeutic approaches to this disease These new targets include signal transduction pathways, oncogenes and growth factors and their receptors. Research has resulted in to the development of inhibitors that target critical elements of these pathways as well as the concept that mutations at one signaling molecule in the pathways (e.g., EGFR, Ras, B-Raf) may prevent sensitivity to an inhibitor targeting a downstream component (e.g., Raf, MEK or PI3K) [20,21,22,23,24,25] These studies indicate that the mutational status of key genes in the pathway (e.g., Ras, B-Raf) will have to be determined in cancer patients before applications of targeted therapy [17]. Cediranib (Recentin, AZD2171; AstraZeneca) Vandetanib (Zactima, ZD6474; AstraZeneca) Foretinib (XL880, GSK1363089; GlaxoSmithKline) Ramucirumab (IMC-1121B; ImClone Systems Inc) Bevacizumab (Avastin; Genetech/Roche) Erlotinib (Tarceva, OSI774; Genetech) Lapatinib (Tyverb, GW572016; GlaxoSmithKline) Gefitinb (Iressa, ZD1839; AtraZeneca) Cetuximab (Erbitux, IMC-C225; Bristol-Meyers Squibb, Merck Serono) OSI-906 (OSI Pharmaceuticals ) Cixutumumab (IMC-A12; ImClone Systems Inc) BIIB022 (Biogen-Idec) AVE1642 (Sanofi-Aventis) Everolimus (RAD001; Novartis) Temsirolimus (Torisel; Wyeth Pharmaceuticals, Inc) AZD8055 (AstraZeneca) ARQ197 (ArQule, Inc) MK-2206 (Merck & Co., Inc.) AZD6244 (ARRY-142886, Selumetinib; AstraZeneca)
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