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Ref Type Journal Article
PMID (28500235)
Authors Savvidou I, Khong T, Cuddihy A, McLean C, Horrigan S, Spencer A
Title β-Catenin Inhibitor BC2059 Is Efficacious as Monotherapy or in Combination with Proteasome Inhibitor Bortezomib in Multiple Myeloma.
Journal Molecular cancer therapeutics
Vol 16
Issue 9
Date 2017 Sep
Abstract Text Currently available treatment options are unlikely to be curative for the majority of multiple myeloma patients, emphasizing a continuing role for the introduction of investigational agents that can overcome drug resistance. The canonical Wnt/β-catenin signaling pathway, essential for self-renewal, growth, and survival, has been found to be dysregulated in multiple myeloma, particularly in advanced stages of disease. This provides the rationale for evaluating the novel β-catenin inhibitor BC2059 as monotherapy and in combination with proteasome inhibitors in vitro and in vivo Here, we show nuclear localization of β-catenin in human myeloma cell lines (HMCL), consistent with activation of the canonical Wnt pathway. BC2059 attenuates β-catenin levels, in both the cytoplasm and the nucleus, reducing the transcriptional activity of the TCF4/LEF complex and the expression of its target gene axin 2. Treatment of HMCL with BC2059 inhibits proliferation and induces apoptosis in a dose-dependent manner. This is also observed in HMCL-stromal cell cocultures, mitigating the protective effect afforded by the stroma. Similarly, BC2059 induces apoptosis in primary multiple myeloma samples in vitro, causing minimal apoptosis on healthy peripheral blood mononuclear cells. Furthermore, it synergizes with the proteasome inhibitor bortezomib both in HMCL and primary multiple myeloma samples. Finally, in xenograft models of human myelomatosis, BC2059 delays tumor growth and prolongs survival with minor on-target side effects. Collectively, these results demonstrate the efficacy of targeting the Wnt/β-catenin pathway with BC2059 both in vitro and in vivo, at clinically achievable doses. These findings support further clinical evaluation of BC2059 for the treatment of multiple myeloma. Mol Cancer Ther; 16(9); 1765-78. ©2017 AACR.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
BC2059 CTNNB1 Inhibitor 26 BC2059 binds to beta-catenin (CTNNB1) and interferes with binding to TBL1 and TBLR1, resulting in increased degradation of beta-catenin and potentially leading to increased apoptosis of tumor cells with activated canonical Wnt signaling (PMID: 28500235).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown multiple myeloma not applicable BC2059 + Bortezomib Preclinical - Patient cell culture Actionable In a preclinical study, the combination of BC2059 and Velcade (bortezomib) worked additively or synergistically in several human multiple myeloma cell lines and primary multiple myeloma cells with activated canonical Wnt signaling in culture (PMID: 28500235). 28500235
Unknown unknown multiple myeloma not applicable BC2059 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with BC2059 decreased proliferation and induced apoptosis of several human multiple myeloma cell lines and primary multiple myeloma cells with activated canonical Wnt signaling in culture, and delayed tumor growth in a multiple myeloma cell line xenograft model (PMID: 28500235). 28500235