Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models

• Published in: PloS one Vol. 10; no. 11; p. e0142612
• Main Authors: Daudigeos-Dubus, Estelle, Le Dret, Ludivine, Lanvers-Kaminsky, Claudia, Bawa, Olivia, Opolon, Paule, Vievard, Albane, Villa, Irène, Pagès, Mélanie, Bosq, Jacques, Vassal, Gilles, Zopf, Dieter, Geoerger, Birgit
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.11.2015; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Aged; Amplification; Angiogenesis; Animals; Anticancer properties; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antitumor activity; Antitumor agents; Apoptosis; Apoptosis - drug effects; Brain; Brain cancer; Brain tumors; Camptothecin - analogs & derivatives; Camptothecin - therapeutic use; Cancer; Cancer therapies; Care and treatment; Cell death; Cell growth; Cell Line, Tumor; Cell Proliferation; Child; Children; Colorectal cancer; Colorectal carcinoma; Combination therapy; Complications and side effects; Connective tissues; Consortia; Deoxyribonucleic acid; DNA; DNA damage; Drug Screening Assays, Antitumor; Endothelial growth factors; Enzyme inhibitors; Experiments; Female; Gastrointestinal cancer; Glioma; Growth inhibition; Health aspects; Humans; In Situ Hybridization, Fluorescence; Influence; Inhibition; Inhibitor drugs; Inhibitors; Irinotecan; Irradiation; Kinases; Laboratories; Liver cancer; Male; Malignancy; MAP kinase; MAP Kinase Signaling System; Medical innovations; Medulloblastoma; Metastasis; Mice; Neoplasm Transplantation; Neoplasms - drug therapy; Neoplasms - metabolism; Neovascularization, Pathologic - drug therapy; Nervous system; Neuroblastoma; Pediatrics; Phenylurea Compounds - therapeutic use; Platelet-derived growth factor; Protein kinase; Pyridines - therapeutic use; Radiation; Regorafenib; Signaling; Solid tumors; Targeted cancer therapy; Tumor cell lines; Tumors; Vascular endothelial growth factor; Vascularization; Xenografts; France; United States > US; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0142612

The multikinase inhibitor regorafenib (BAY 73-4506) exerts both anti-angiogenic and anti-tumorigenic activity in adult solid malignancies mainly advanced colorectal cancer and gastrointestinal stromal tumors. We intended to explore preclinically the potential of regorafenib against solid pediatric malignancies alone and in combination with anticancer agents to guide the pediatric development plan. In vitro effects on cell proliferation were screened against 33 solid tumor cell lines of the Innovative Therapies for Children with Cancer (ITCC) panel covering five pediatric solid malignancies. Regorafenib inhibited cell proliferation with a mean half maximal growth inhibition of 12.5 μmol/L (range 0.7 μmol/L to 28 μmol/L). In vivo, regorafenib was evaluated alone at 10 or 30 mg/kg/d or in combination with radiation, irinotecan or the mitogen-activated protein kinase kinase (MEK) inhibitor refametinib against various tumor types, including patient-derived brain tumor models with an amplified platelet-derived growth factor receptor A (PDGFRA) gene. Regorafenib alone significantly inhibited tumor growth in all xenografts derived from nervous system and connective tissue tumors. Enhanced effects were observed when regorafenib was combined with irradiation and irinotecan against PDGFRA amplified IGRG93 glioma and IGRM57 medulloblastoma respectively, resulting in 100% tumor regressions. Antitumor activity was associated with decreased tumor vascularization, inhibition of PDGFR signaling, and induction of apoptotic cell death. Our work demonstrates that regorafenib exhibits significant antitumor activity in a wide spectrum of preclinical pediatric models through inhibition of angiogenesis and induction of apoptosis. Furthermore, radio- and chemosensitizing effects were observed with DNA damaging agents in PDGFR amplified tumors.