Abstract 4526: BIBF1120, an investigational triple angiokinase inhibitor, in combination with inhibitors of mTOR signaling shows potent antitumor activity in preclinical models of sarcoma

Abstract

Abstract BIBF1120 (Nintedanib), an investigational potent small molecule angiokinase inhibitor, selectively binds to and blocks receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptor, (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR). Nintedanib has shown promising results in preclinical as well as clinical studies of non-small cell lung cancer, colorectal, ovarian cancer and other solid tumors. We tested the in vitro anti-proliferative activity of BIBF1120 in a panel of sarcoma cell lines including malignant peripheral nerve sheath tumor (MPNST), synovial (SYO-I), Ewing's (CHP100), osteo (SaOS2) and liposarcoma (LS141). Our results indicate that when compared to other potent RTK inhibitors such as Imatinib and Pazopanib, BIBF1120 is highly efficient at nanomolar to low micromolar concentrations in blocking proliferative activity of sarcoma cell lines, specifically, SYO-I and MPNST, which are highly dependent on PDGFR signaling. Western blot analysis to test the efficacy of BIBF1120 confirmed significant blockade of RTK signaling pathways. Ras activation and/or activation of mitogen activated protein kinase (MAPK) pathway has been shown to be critical in sarcomas including MPNST and synovial sarcomas. Unlike Imatinib and Pazopanib, BIBF1120 also blocked MAPK signaling pathway as demonstrated by p-ERK1/2 blockade. In addition to the RTKs, mTOR (mammalian Target of Rapamycin) protein plays a key role in AKT activation and downstream survival signaling. Combination of RTK blockade by BIBF1120 and mTOR blockade by TORC1 inhibitor rapamycin resulted in significantly stronger inhibition of in vitro cellular proliferation compared to single agent treatments. Taken together, our data strongly supports further clinical research of BIBF1120 in sarcoma. Combining potent inhibitors of tyrosine kinase signaling, MAPK signaling and inhibitors of mTOR pathway such as rapamycin could provide a new therapeutic approach in this disease. Citation Format: Parag P. Patwardhan, Elgilda Musi, Kathryn S. Ivy, Natalie Giovino, Gary K. Schwartz. BIBF1120, an investigational triple angiokinase inhibitor, in combination with inhibitors of mTOR signaling shows potent antitumor activity in preclinical models 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 4526. doi:10.1158/1538-7445.AM2014-4526