Abstract C144: Treatment with β-catenin antagonist BC2059 exhibits single agent efficacy and exerts superior activity with tyrosine kinase inhibitor (TKI) or histone deacetylase (HDAC) inhibitor against human AML, CML, and myeloproliferative neoplasm (MPN) progenitor cells.

The canonical WNT-β-catenin signaling is essential to the cellular processes of self-renewal and growth, as well as required for self-renewal of leukemia stem. The multi-protein degradation complex for β-catenin is often inactivated in transformed hematopoietic progenitor cells. This results in the preservation, nuclear translocation and interaction of β-catenin with the T-cell factor (TCF)/lymphoid enhancer factor (LEF) transcription factor, which regulates the expression of genes such as cyclin D1, MYC and survivin. BC2059 (β-Cat Pharmaceuticals) is a potent small molecule, anthraquinone oxime-analog inhibitor of the WNT-β-catenin pathway. Treatment with BC2059 mediates the degradation and attenuated levels of β-catenin. In the present studies, we determined the activity of BC2059 in human cultured and primary AML, CML and advanced MPN versus normal cells. Exposure to 50 to 100 nM of BC2059 induced cell cycle G1 phase accumulation and apoptosis (40 to 80%) of the cultured AML cells (HL-60 and OCI-AML3), MPN HEL92.1.7 (HEL) and UKE1 cells expressing the mutant JAK2V617F, as well as of the CML K562 and LAMA-84 cells expressing BCR-ABL. BC2059 treatment also induced apoptosis of CD34+ primary MPN cells from patients with advanced MPN expressing mutant JAK2, as well as of primary CD34+ AML and CML progenitor cells. In contrast, BC2059 did not induce significant apoptosis of normal CD34+ progenitor cells. Exposure to BC2059 attenuated both β-catenin protein levels (significantly restored by co-treatment with the proteasome inhibitor) and the activity of the LEF1/TCF4 transcription factor, associated with reduced levels of cyclin D1, MYC and survivin in the cell lysates of BC2059-treated AML, CML and MPN cells. Following the tail vein infusion of HEL cells and establishment of MPN, NOD-SCID mice were treated with 15 or 20 mg/kg of BC2059 administered b.i.w for three weeks via the tail vein. As compared to the control, BC2059-treated mice demonstrated significantly improved survival (p 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 C144.