New molecularly targeted therapies against advanced hepatocellular carcinoma: From molecular pathogenesis to clinical trials and future directions

Abstract

Hepatocellular carcinoma (HCC) can be lethal due to its aggressive course and lack of effective systemic therapies for advanced disease. Sorafenib is the only systemic therapy that has demonstrated an overall survival benefit in patients with advanced HCC, and new agents for treatment of advanced HCC are needed. The multiple pathways involved in HCC oncogenesis, proliferation and survival provide many opportunities for the development of molecularly targeted therapies. Molecular targets of interest have expanded from angiogenesis to cancer cell-directed oncogenic signaling pathways for treatment of advanced HCC. Agents targeting vascular endothelial growth factor receptor, epidermal growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, c-mesenchymal-epithelial transition factor-1 and mammalian target of rapamycin signaling have been actively explored. This article focuses on the evaluation of molecular agents targeting pathogenic HCC and provides a review of recently completed phase III drug studies (e.g. involving sorafenib, sunitinib, brivanib, linifanib, erlotinib, everolimus, ramucirumab or orantinib) and ongoing drug studies (e.g. involving lenvatinib, regorafenib, tivantinib or cabozantinib) of molecularly targeted agents in advanced HCC, including a brief description of the biologic rationale behind these agents.

Molecular Targeted Therapy for Hepatocellular Carcinoma: Present Status and Future Directions

“…However, neither targeted agents nor regimens other than sorafenib have yet significantly improved the OS in HCC patients with advanced disease status, mainly due to a lack of efficacy, flaws in trial design, and toxicity. 12) HCC is a highly heterogeneous disease driven by its complex pathogenesis, which involves diverse genetic dysregulations in numerous functional pathways. Drugs designed to act against individual molecular targets may not be able to effectively combat HCC's multigenicity.…”

“…Recent advances in molecular pathogenesis studies have defined numerous molecular targets that are critical to HCC development, progression, and metastasis, including vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), c-mesenchymal-epithelial transition factor-1 (c-Met), mammalian target of rapamycin (mTOR) and histone deacetylases (HDACs). [11][12][13] New treatments of inhibitors targeting several of these critical pathways are in development. In this review, we describe the key genes and pathways involved in hepatocarcinogenesis, as well as the ongoing clinical trials using targeted inhibitors, and suggest new possibilities for developing therapeutic options for HCC.…”

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

“…Sorafenib is a tyrosine kinase inhibitor widely used for the treatment of advanced HCC, and many other molecular-targeted drugs are now in development [79] . However its effect is still limited in many patients and the appearance of drug-resistance is a significant problem.…”

Hepatocellular Carcinoma: Past and Future of Molecular Target Therapy

“…Activated endothelial cells break down extracellular matrix and basement membrane which result in release of angiogenic factors which includes vascular endothelial growth factor (VEGF), basic fibroblast growth factors (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta (TGFβ) [45]. These factors in turn activate endothelial cells through receptor tyrosine kinases (RTK) and the RAS/RAF/MEK/ERK pathway and PI3K pathway which leads to proliferation and migration of endothelial cells to form a new tubular structure and lumen for new vessels [45,46]. These new vessels are different from normal vessel in the aspect of leaky vessel, incomplete basal membrane, irregular diameter, and branching pattern [45].…”