Abstract
Abstract 3038
Multiple myeloma (MM), one of the most incurable hematological malignancies in adults, is a disorder of plasma cells characterized by accumulation of clonal proliferation of malignant plasma cells in the bone marrow (BM). Overexpression of beta-catenin, the downstream effector of the canonical Wnt signaling pathway, has been reported in both MM cell lines and patient samples. Activated Wnt signaling pathway has also been reported to play a critical role in progression of MM cell proliferation, thus highlighting the need for new therapeutic approaches, particularly those targeting Wnt molecular pathway. Here we report the discovery of a novel inhibitor of Wnt signaling CWP232291, which promotes degradation of beta-catenin. CWP232291 exhibits potent growth inhibitory activity in several MM cell lines (RPMI-8226, OPM-2, NCI-H929, JJN3, and EJM) with IC50 values of 13 – 73 nM. The inhibitory activity of CWP232291 on Wnt signaling is demonstrated by reporter gene assay and by its effect in down-regulation of Wnt target genes. Using HEK293 cells, CWP232291 treatment dose dependently reduces promoter activity of TOPflash induced by Wnt-3a-Conditioned Media, at a calculated IC50 value of 273 nM. Furthermore, MM cells treated with CWP232291 show downregulated expression of Wnt target genes such as survivin by triggering degradation of beta-catenin. Treatment of these cells with CWP232291 results in activation of caspase-3 and PARP cleavage, indicating induction of apoptosis. To investigate the potential in vivo anti-tumor efficacy of CWP232291, we utilized two MM tumor bearing mice models. Daily or intermittent intravenous (i.v.) administration of CWP232291 led to significant tumor growth inhibition (TGI) in OPM-2 (50 mg/kg, qdx5: regression and 100 mg/kg, biw: 95% TGI) and RPMI-8226 (100 mg/kg, qdx5: regression and 100 mg/kg tiw: 80% TGI) xenograft model with no obvious change in body weight. The anti-tumor efficacies of CWP232291 were dose-dependent and had strong correlations with degradation of beta-catenin in the tumor samples. Potent induction of apoptosis through cleavage of Caspase-3 and PARP and significant decrease of plasma M protein levels in OPM-2 tumor bearing mice were detected as early as 2 and up to 24 hours after single i.v. administration of CWP232291. Taken together, these data clearly demonstrate the impressive anti-tumor profile of CWP232291 with a good therapeutic window and suggest a potential therapeutic application of CWP232291 for the treatment of MM.
Disclosures:
Cha: Choongwae Pharma Corp.: Employment. Jung:Choongwae Pharma Corp.: Employment. Lee:Choongwae Pharma Corp.: Employment. Briaud:Theriac Pharmaceutical Corp.: Employment. Tenzin:Theriac Pharmaceutical Corp.: Employment. Jung:Choongwae Pharma Corp.: Employment. Pyon:Choongwae Pharma Corp.: Employment. Lee:Choongwae Pharma Corp.: Employment. Chung:Choongwae Pharma Corp.: Employment. Lee:Choongwae Pharma Corp.: Employment. Oh:Choongwae Pharma Corp.: Employment. Jung:Choongwae Pharma Corp.: Employment. Pai:Choongwae Pharma Corp.: Employment. Emami:Theriac Pharmaceutical Corp.: Employment.
The Wnt signaling pathway in tumorigenesis, pharmacological targets, and drug development for cancer therapy
