Reference Detail

Ref Type

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	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget			2015 Dec 10	4093-109	Oncotarget

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
Sitravatinib	Sitravatinib	7	4

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Sitravatinib		MGCD516	AXL Inhibitor 30 DDR1 Inhibitor 10 DDR2 inhibitor 7 KIT Inhibitor 57 MERTK Inhibitor 13 MET Inhibitor 59 RET Inhibitor 52 Trk Receptor Inhibitor (Pan) 31 TYRO3 Inhibitor 8 VEGFR Inhibitor (Pan) 36	Sitravatinib (MGCD516) 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, PMID: 32525624).

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