Abstract
Abstract The hedgehog (Hh) pathway is a critical embryonic signaling cascade regulating cell growth, proliferation and differentiation. Hh signaling is significantly less active in adult tissues, where its primary role appears to be the maintenance of stem cell populations in skin and the central nervous system. Smoothened (Smo), a 7-pass transmembrane receptor with a GPCR-like structure, is a key component of the Hh signaling pathway, the activity of which is suppressed by the 12-pass transmembrane protein Patched (Ptch). Therefore, components of the Hh pathway (such as Shh, SMO, and GLI1/2) are viable therapeutic targets for anti-tumor strategy. We report here the in vivo effects of a potent Smo antagonist DCBCO1303 for the treatment of medulloblastoma and cholagiocarcinoma animal tumor model. DCBCO1303 demonstrated Hh signaling pathway antagonist activity in a 293 cell-based Gli-luciferase inhibition assay upon agonist treatment (IC50 = 3.5 nM), and retains inhibition activity against the Smo wild-type and D473H mutant responsible for resistance to GDC-0449 in medulloblastoma patients with IC50 of 5.1 and 43.7nM, respectively. DCBCO1303 potently suppress Gli1 expression in HEPM cells with IC50 of 2.3 nM. Treatment of a medulloblastoma allograft model with daily oral dosing from 1.25 to 40 mg/kg of DCBCO1303 for 10 days leads to dose responsive antitumor activity with tumor regressions occurring at 40 mg/kg.(Gli 1 mRNA inhibition correlated with tumor growth inhibition). DCBCO1303 was also highly efficacious against the growth of cholangiocarcinoma xenograft tumors. The DCBCO1303 can therefore be evaluated further and serve as a drug development candidate for treatment of Hh pathway-driven cancers. Citation Format: Ying-Shuan E Lee, Mann-Yan Kuo, Pei-Yi Tsai, Chia Wei Liu, Win Yin Wei. A Smo inhibitor DCBCO1303 with potent Hedgehog signaling pathway antagonist activity is highly active in animal tumor model of medulloblastoma and cholangiocarcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C046. doi:10.1158/1535-7163.TARG-19-C046
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have