Regorafenib (BAY 73-4506): Antitumor and antimetastatic activities in preclinical models of colorectal cancer

Autor: Peter Ellinghaus, Robert Adams, Tina Müller, Dieter Zopf, Jens Hoffmann, Scott Wilhelm, André Rosenthal, Roberta Schmieder, Arne Scholz, Ajay Bhargava, Karl-Heinz Thierauch, Michael Becker, Nicole Kahmann
Jazyk: angličtina
Rok vydání: 2014
Předmět:
CD31
Male
Cancer Research
Organoplatinum Compounds
Colorectal cancer
Pyridines
Pharmacology
chemistry.chemical_compound
Mice
Random Allocation
0302 clinical medicine
Liver Neoplasms
Experimental
Antineoplastic Combined Chemotherapy Protocols
Neoplasm Metastasis
0303 health sciences
3. Good health
CRC
Oxaliplatin
Oncology
030220 oncology & carcinogenesis
Immunohistochemistry
Cancer Therapy
Female
multikinase inhibitor
Colorectal Neoplasms
medicine.drug
Combination therapy
Mice
Nude
Cell Growth Processes
Irinotecan
03 medical and health sciences
Regorafenib
Cell Line
Tumor
medicine
Animals
Humans
030304 developmental biology
antimetastasis
business.industry
Phenylurea Compounds
Kinase insert domain receptor
medicine.disease
Vascular Endothelial Growth Factor Receptor-3
Vascular Endothelial Growth Factor Receptor-2
Xenograft Model Antitumor Assays
digestive system diseases
antitumorigenesis
Mice
Inbred C57BL
chemistry
Drug Resistance
Neoplasm
Cancer research
regorafenib
Camptothecin
business
Zdroj: International Journal of Cancer. Journal International du Cancer
ISSN: 1097-0215
0020-7136
Popis: Regorafenib, a novel multikinase inhibitor, has recently demonstrated overall survival benefits in metastatic colorectal cancer (CRC) patients. Our study aimed to gain further insight into the molecular mechanisms of regorafenib and to assess its potential in combination therapy. Regorafenib was tested alone and in combination with irinotecan in patient-derived (PD) CRC models and a murine CRC liver metastasis model. Mechanism of action was investigated using in vitro functional assays, immunohistochemistry and correlation with CRC-related oncogenes. Regorafenib demonstrated significant inhibition of growth-factor-mediated vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR3 autophosphorylation, and intracellular VEGFR3 signaling in human umbilical vascular endothelial cells (HuVECs) and lymphatic endothelial cells (LECs), and also blocked migration of LECs. Furthermore, regorafenib inhibited proliferation in 19 of 25 human CRC cell lines and markedly slowed tumor growth in five of seven PD xenograft models. Combination of regorafenib with irinotecan significantly delayed tumor growth after extended treatment in four xenograft models. Reduced CD31 staining indicates that the antiangiogenic effects of regorafenib contribute to its antitumor activity. Finally, regorafenib significantly delayed disease progression in a murine CRC liver metastasis model by inhibiting the growth of established liver metastases and preventing the formation of new metastases in other organs. In addition, our results suggest that regorafenib displays antimetastatic activity, which may contribute to its efficacy in patients with metastatic CRC. Combination of regorafenib and irinotecan demonstrated an increased antitumor effect and could provide a future treatment option for CRC patients. What's new? Regorafenib is a multikinase inhibitor with antiangiogenic activity recently approved in the US and in Europe for the treatment of metastatic colorectal cancer in patients who failed previous therapies. Here, a research team led by Bayer Pharma AG, the discoverer of the drug, confirms inhibition of key mediators of angiogenesis and lymphangiogenesis (VEGFR2 and VEGFR3) as the potential antiangiogenic mechanism of action of the drug. Regorafenib further inhibited growth of established and prevented formation of new liver metastases, and in combination with the chemotherapeutic drug irinotecan led to significant tumor growth delay in four patient-derived colorectal cancer xenograft models. The authors speculate that combination treatments including regorafenib may provide novel therapeutic opportunities for patients with therapy-resistant colorectal cancer.
Databáze: OpenAIRE
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