Hepatocellular carcinoma (HCC) is a complex biological process and is often diagnosed at advanced stages with no effective treatment options. With advances in tumor biology and molecular genetic profiling, several different signaling pathways and molecular mechanisms have been identified as responsible for initiating and promoting HCC. Targeting these critical pathways, which include the receptor tyrosine kinase pathways, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK), the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), the Wnt/β-catenin signaling pathway, the ubiquitin/proteasome degradation and the hedgehog signaling pathway has led to the identification of novel therapeutics for HCC treatment. In this review, we elaborated on our current understanding of the signaling pathways involved in the development and initiation of HCC and anticipate the potential targets for therapeutic drug development.

https://www.mdpi.com/2072-6694/12/2/491/pdf

Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma.

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.

/pdf/targeted-therapy-for-hepatocellular-carcinoma-novel-agents-1pidqekaaz.pdf

Targeted therapy for hepatocellular carcinoma: novel agents on the horizon

The success of sorafenib has spurred an explosive increase of clinical trials testing novel molecular targets and other agents in the treatment of hepatocellular carcinoma (HCC). The paradigm of the studies has been characterized by three noticeable changes. First, the molecular targets of interest have expanded from angiogenesis to cancer cell-directed oncogenic signaling pathways for advanced HCC treatment. Agents targeting EGFR, FGFR, PI3K/Akt/mTOR, TGF-β, c-Met, MEK, IGF signaling, and histone deacetylase have been actively explored. Second, the target indication has shifted from advanced stage to early or intermediate stages of disease. The feasibility of combining locoregional therapies and targeted agents, and the use of novel agents after curative treatments are currently under active investigation. Finally, the therapeutic strategy has shifted from monotherapy to combination targeted therapy. We aim to provide a comprehensive overview of newly disclosed and ongoing clinical trials for the treatment of HCC.

/pdf/clinical-trials-in-hepatocellular-carcinoma-an-update-3ka44knfka.pdf

Clinical trials in hepatocellular carcinoma: an update.

Hepatocellular carcinoma is (HCC) the most common primary malignancy of the liver in adults. It is also the fifth most common solid cancer worldwide and the third leading cause of cancer-related deaths. Treatment options for HCC include liver transplantation, surgical resection, locoregional therapies and chemotherapy. The median survival time of patients following the diagnosis of unresectable disease is approximately 6-20 months, whereas the 5-year survival is less than 5%. Given the projected increase in incidence of HCC due to hepatitis C virus infection and obesity related cirrhosis, there is an urgent need for more intensive research in this cancer. In this article, we review the systemic options available for patients with HCC, its molecular pathogenesis and future therapeutic directions with special emphasis on immune-based and molecularly-targeted therapy.

Hepatocellular carcinoma: systemic therapies and future perspectives.

https://www.jto.org/article/S1556-0864(15)33248-2/pdf

A Phase I/II Study of Erlotinib in Combination with the Anti-Insulin-Like Growth Factor-1 Receptor Monoclonal Antibody IMC-A12 (Cixutumumab) in Patients with Advanced Non-small Cell Lung Cancer

4043 Background: C is an anti-IGF-1R monoclonal antibody. IGF-IR is implicated in hepatic carcinogenesis. A phase I study of C yielded a partial response in HCC. Methods: Patients (pts) with advanc...

Phase II study of cixutumumab (IMC-A12, NSC742460; C) in hepatocellular carcinoma (HCC).

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Phase II study of cixutumumab (IMC-A12, NSC742460; C) in hepatocellular carcinoma (HCC).