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

TLDR

Sarcomas are rare, aggressive mesenchymal tumors with a median survival of 10–18 months for metastatic disease, driven in part by mutations or overexpression of RTKs such as c‑Met, PDGFR, c‑Kit, and IGF1‑R. The study aims to evaluate MGCD516, a novel multi‑RTK inhibitor, for its ability to block sarcoma cell growth. The authors tested MGCD516 in vitro and in mouse xenograft models to assess its anti‑tumor efficacy. MGCD516 significantly blocked phosphorylation of driver RTKs, inhibited sarcoma cell proliferation in vitro, suppressed tumor growth in xenografts, and outperformed imatinib and crizotinib, supporting its further clinical development.

Abstract

// Parag P. Patwardhan 1, * , Kathryn S. Ivy 1, * , Elgilda Musi 1 , Elisa de Stanchina 2 , Gary K. Schwartz 1, 3 1 Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA 2 Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY, USA 3 Department of Medicine, Division of Hematology/Oncology, Columbia University Medical Center, New York, NY, USA * These authors have contributed equally to this work Correspondence to: Parag P. Patwardhan, e-mail: [e-mail] Keywords: MGCD516, Sitravatinib, tyrosine kinase, imatinib, crizotinib Received: September 03, 2015      Accepted: November 25, 2015      Published: December 10, 2015 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.