Abstract 1751: Preclinical development of a novel multi-targeted kinase inhibitor, MG516, for the treatment of sarcoma

Abstract

Abstract Receptor tyrosine kinases (RTKs) are key regulators of tumor development as well as metastasis, aiding in the epithelial-mesenchymal transition, migration and angiogenesis. RTK signaling pathways such as VEGFR, PDGFR, and c-Met have been shown to be critical for cell survival, proliferation and metastasis in sarcomas. RTK inhibitors have been used with moderate success to block tumor cell survival and proliferation, however, internal compensatory signaling pathways give rise to drug resistance in a majority of cases. MG516, is a novel multi-targeted tyrosine kinase inhibitor that blocks RTK signaling pathways including c-Met, Ephrin receptors (Eph), and VEGFR with low nanomolar IC50 values. We evaluated the RTK inhibition profile and anti-proliferative effect of MG516 in a diverse panel of sarcoma cell lines including malignant peripheral nerve sheath tumor (MPNST), Ewing's sarcoma (A673) and leiomyosarcoma (SKLMS). MG516 inhibits tumor cell proliferation in vitro in a dose dependent manner with IC50s ranging from 500 to 2500 nM. We used a human phopho-RTK array kit, which allows the screening of 49 different phosphorylated human RTKs, in a panel of sarcoma cell lines. Our data indicates that MG516 provides robust blockade of a wide panel of RTKs including c-Met, EphB3, EphA10, PDGFR-β, Axl and IGF1-R at nanomolar to low micromolar concentrations. Western blot analysis showed a significant blockade of downstream effectors including p-AKT, p-FAK and p-STAT3. These results demonstrate the efficacy of MG516 in blocking RTKs and their downstream signaling pathways. Since PDGFR-β, c-Met and IGF1-R have been shown to be involved in tumor initiation, development and metastasis in a variety of sarcoma subtypes, our data would strongly support further development of MG516 as a novel agent in the treatment of sarcomas. Citation Format: Kathryn S. Ivy, Parag P. Patwardhan, Gary K. Schwartz. Preclinical development of a novel multi-targeted kinase inhibitor, MG516, for the treatment of sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1751. doi:10.1158/1538-7445.AM2014-1751