Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers

• Published in: Experimental & molecular medicine 2019, 51(0), , pp.1-15
• Main Authors: Fondevila, Flavia, Méndez-Blanco, Carolina, Fernández-Palanca, Paula, González-Gallego, Javier, Mauriz, José L.
• Format: Article
• Language: English
• Subjects: 631/67/1059/602; 631/67/1504/1610; 631/67/1504/1885; 631/67/70; Angiogenesis; Antineoplastic Agents - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Chemotherapy; Clinical trials; Colorectal cancer; Colorectal carcinoma; Combined Modality Therapy; Gastrointestinal cancer; Gastrointestinal Neoplasms - drug therapy; Gastrointestinal Neoplasms - pathology; Hepatocellular carcinoma; Humans; Liver - drug effects; Liver - pathology; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Medical Biochemistry; Molecular Medicine; Molecular modelling; Patients; Phenylurea Compounds - therapeutic use; Protein Kinase Inhibitors - therapeutic use; Pyridines - therapeutic use; Review; Review Article; Sorafenib - therapeutic use; Stem Cells; Targeted cancer therapy; Tumor cells; Tumor Microenvironment - drug effects; Tumorigenesis; Tumors; Tyrosine; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-019-0308-1

Regorafenib is a sorafenib-derived chemotherapy drug belonging to the multikinase inhibitor family. This agent effectively targets a wide range of tyrosine kinases involved in cancer biology, such as those implicated in oncogenesis, angiogenesis, and tumor microenvironment control. The beneficial effects of regorafenib in clinical trials of patients who suffer from advanced hepatocellular carcinoma (HCC), colorectal cancer (CRC) or gastrointestinal stromal tumors (GISTs) refractory to standard treatments led to regorafenib monotherapy approval as a second-line treatment for advanced HCC and as a third-line treatment for advanced CRC and GISTs. Multiple in vitro and in vivo studies have been performed over the last decade to reveal the molecular mechanisms of the favorable actions exerted by regorafenib in patients. Given the hypothetical loss of sensitivity to regorafenib in tumor cells, preclinical research is also searching for novel therapeutic approaches consisting of co-administration of this drug plus other agents as a strategy to improve regorafenib effectiveness. This review summarizes the anti-tumor effects of regorafenib in single or combined treatment in preclinical models of HCC, CRC and GISTs and discusses both the global and molecular effects that account for its anti-cancer properties in the clinical setting. Regorafenib: Combination therapy in liver and gastrointestinal cancer The cancer drug regorafenib exhibits a broad range of anti-tumor activities that could be enhanced by combination with other treatments. A team led by José L. Mauriz from the University of León, Spain, review the ways in which regorafenib, blocking several enzymes involved in cancer biology, has been shown to shrink tumors in different models of liver, colon and gastrointestinal cancer. Its mechanisms of action include blockade of new blood vessel formation, induction of cell death and modulation of the immune microenvironment. Research studies show that co-administration of regorafenib with other drugs directed at various molecular targets or immune pathways produces synergistic effects against cancer cells. The preclinical data highlights the potential of combination drug regimens to improve outcomes among patients eligible for regorafenib treatment.