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PMID (26675259)
Authors Patwardhan PP, Ivy KS, Musi E, de Stanchina E, Schwartz GK
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.
Journal Oncotarget
Vol
Issue
Date 2015 Dec 10
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
MGCD516 MGCD516 8 2
Drug Name Trade Name Synonyms Drug Classes Drug Description
MGCD516 Sitravatinib AXL Inhibitor 27 DDR1 Inhibitor 8 DDR2 inhibitor 7 KIT Inhibitor 50 MERTK Inhibitor 9 MET Inhibitor 51 RET Inhibitor 39 Trk Receptor Inhibitor (Pan) 23 TYRO3 Inhibitor 8 VEGFR Inhibitor (Pan) 32 MGCD516 (Sitravatinib) inhibits several receptor tyrosine kinases including AXL, MET, KIT, VEGFR1-3, TYRO3, RET family members, TRK family members, DDR, and Eph family members, resulting in abrogation of downstream signaling and decreased cell proliferation in tumors overexpressing the target proteins (PMID: 26675259, PMID: 30501104).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown liposarcoma not applicable MGCD516 Preclinical - Cell line xenograft Actionable In a preclinical study, MGCD516 blocked cell proliferation of a human liposarcoma cell line in culture and repressed tumor growth in xenograft models (PMID: 26675259). 26675259