Molecular targeted therapy for advanced hepatocellular carcinoma: current status and future perspectives

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Sorafenib, a multikinase inhibitor, is the first drug to improve survival in advanced hepatocellular carcinoma (HCC).
• Its mechanism targets vascular endothelial growth factor (VEGF)-mediated angiogenesis, marking a shift towards molecular targeted therapy (MTT) for HCC.
• However, resistance to VEGF signaling-targeted MTT develops rapidly, limiting long-term efficacy.

Purpose of the Study:

• To review current strategies for overcoming resistance to VEGF signaling-targeted MTT in HCC.
• To highlight the need for improved methodologies in pharmacodynamic assessment, patient selection, and target identification for MTT development.
• To encourage patient selection based on tumor molecular profiles and the use of correlative biomarker studies in clinical trials.

Main Methods:

• Literature review of current research on HCC molecular targeted therapy.
• Analysis of resistance mechanisms to VEGF signaling inhibitors.
• Discussion of strategies to enhance MTT efficacy and patient selection.

Main Results:

• VEGF signaling-targeted MTT for HCC offers limited duration of benefit due to rapid resistance.
• Investigational strategies include inhibiting compensatory pro-angiogenic pathways, bone marrow-derived circulating endothelial progenitors, and other oncogenic pathways.
• Combination or multi-target agents may increase efficacy but also toxicities.

Conclusions:

• Overcoming resistance is crucial for advancing MTT in HCC.
• Improved methods for patient selection and biomarker studies are essential for developing novel MTT.
• Personalized medicine approaches based on individual tumor molecular signatures are recommended for future clinical trials.