title: Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models.
abstract: 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.
authors.affiliation: Université Paris-Sud 11, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France.|CNRS, Vectorology and Anticancer Therapeutics, UMR 8203, Orsay, France.|Gustave Roussy, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Daudigeos-Dubus
authors.affiliation: Université Paris-Sud 11, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France.|CNRS, Vectorology and Anticancer Therapeutics, UMR 8203, Orsay, France.|Gustave Roussy, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Le Dret
authors.affiliation: University Children's Hospital, Department of Pediatric Hematology and Oncology, Münster, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanvers-Kaminsky
authors.affiliation: PFEP (Plateforme d'évaluation préclinique), Gustave Roussy, Villejuif, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Bawa
authors.affiliation: PFEP (Plateforme d'évaluation préclinique), Gustave Roussy, Villejuif, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Opolon
authors.affiliation: Tribvn, Châtillon, France.
authors.forename: Albane
authors.initials: A
authors.lastname: Vievard
authors.affiliation: Pathology Laboratory, Gustave Roussy, Villejuif, France.
authors.forename: Irène
authors.initials: I
authors.lastname: Villa
authors.affiliation: Department of Neuropathology, Sainte-Anne's Hospital, Paris, France.|Paris Descartes University, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Pagès
authors.affiliation: Pathology Laboratory, Gustave Roussy, Villejuif, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Bosq
authors.affiliation: Université Paris-Sud 11, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France.|CNRS, Vectorology and Anticancer Therapeutics, UMR 8203, Orsay, France.|Gustave Roussy, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.affiliation: Bayer Pharma Aktiengesellschaft, Berlin, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Zopf
authors.affiliation: Université Paris-Sud 11, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France.|CNRS, Vectorology and Anticancer Therapeutics, UMR 8203, Orsay, France.|Gustave Roussy, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France.
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002648:Child; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D000077146:Irinotecan; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib; D000077146:Irinotecan; D002166:Camptothecin