Targeted therapy for hepatocellular carcinoma: novel agents on the horizon

Abstract

Melchiorre Cervello 1 , James A. McCubrey 2 , Antonella Cusimano 1 , Nadia Lampiasi 1 , Antonina Azzolina 1 , Giuseppe Montalto 1,3 1 Institute of Biomedicine and Molecular Immunology, “Alberto Monroy” National Research Council (C.N.R.) Via Ugo La Malfa 153, 90146 Palermo, Italy 2 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, 600 Moye Blvd, Greenville NC 27858, USA 3 Department of Internal Medicine and Specialties, University of Palermo, Via del Vespro 143, 90127 Palermo, Italy Received: March 22, 2012; Accepted: March 31, 2011; Published: March 31, 2012; Keywords: HCC, targeted therapy, VEGF, Ras/Raf/MEK/ERK, PI3K/Akt/PTEN/mTOR, signal transduction inhibitors, cancer Correspondence: Melchiorre Cervello, email: // // 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.