title: Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma.
abstract: Sarcomas are rare but highly aggressive mesenchymal tumors with a median survival of 10-18 months for metastatic disease. Mutation and/or overexpression of many receptor tyrosine kinases (RTKs) including c-Met, PDGFR, c-Kit and IGF1-R drive defective signaling pathways in sarcomas. MGCD516 (Sitravatinib) is a novel small molecule inhibitor targeting multiple RTKs involved in driving sarcoma cell growth. In the present study, we evaluated the efficacy of MGCD516 both in vitro and in mouse xenograft models in vivo. MGCD516 treatment resulted in significant blockade of phosphorylation of potential driver RTKs and induced potent anti-proliferative effects in vitro. Furthermore, MGCD516 treatment of tumor xenografts in vivo resulted in significant suppression of tumor growth. Efficacy of MGCD516 was superior to imatinib and crizotinib, two other well-studied multi-kinase inhibitors with overlapping target specificities, both in vitro and in vivo. This is the first report describing MGCD516 as a potent multi-kinase inhibitor in different models of sarcoma, superior to imatinib and crizotinib. Results from this study showing blockade of multiple driver signaling pathways provides a rationale for further clinical development of MGCD516 for the treatment of patients with soft-tissue sarcoma.
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
authors.forename: Parag P
authors.initials: PP
authors.lastname: Patwardhan
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Ivy
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
authors.forename: Elgilda
authors.initials: E
authors.lastname: Musi
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.|Department of Medicine, Division of Hematology/Oncology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C000611865:sitravatinib; D020794:Receptor Protein-Tyrosine Kinases
keywords: MGCD516; Sitravatinib; crizotinib; imatinib; tyrosine kinase