Abstract C148: SC144: The first orally active small molecule gp130 inhibitor for the treatment of ovarian cancer.

Abstract

Abstract Ovarian cancer is one of the leading causes of cancer-related death in women in the United States. The gp130/Stat3 signaling axis plays an important role in carcinogenesis and drug resistance in a wide variety of human cancers, including ovarian cancer. As a downstream effector of gp130, Stat3 is constitutively activated and plays a critical role in ovarian cancer progression. In this study, we showed that a novel selective small molecule gp130 inhibitor, SC144, suppressed ovarian cancer progression both in vitro and in vivo. SC144 treatment in vitro induced gp130 phosphorylation and deglycosylation, resulting in the downregulation of surface-bound gp130 and the abrogation of gp130-associated Stat3 activation. In addition, SC144 selectively inhibited the downstream signaling activation induced by gp130 substrates, including IL-6 and LIF, whereas SC144 did not exhibit detectable effects on the downstream signaling activation induced by non-gp130 substrates, including IFN-γ, SDF-1α, and PDGF. Protein expression regulated by the gp130/Stat3 axis in OVCAR-8 cells was also down-regulated after SC144 treatment, including Bcl-2, Bcl-XL, survivin, cyclin D1, MMP-7, gp130 and Ape1/Rel-1. In vivo, SC144 significantly inhibited tumor growth in a mouse xenograft model of human ovarian cancer via i.p. or p.o. administration. After SC144 treatment for two months, gp130, Bcl-2, Bcl-XL, MMP-7 and Ape1/Ref-1 protein levels were substantially decreased in the tumor site in the treatment group compared with the control group. Our results further suggest gp130 is a novel drug target for ovarian cancer therapy, and the development of small molecule inhibitors of gp130 can help interrogate this unique signaling pathway in human diseases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C148.