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 .

中文翻译：

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β-连环蛋白抑制剂BC2059可有效用于多发性骨髓瘤的单药治疗或与蛋白酶体抑制剂硼替佐米联用。

对于大多数多发性骨髓瘤患者而言，目前可用的治疗方案不太可能治愈，强调了可以克服耐药性的研究药物的持续作用。已发现对于自我更新，生长和存活必不可少的经典Wnt /β-catenin信号通路在多发性骨髓瘤，尤其是疾病的晚期阶段中失调。这提供了评估新型β-catenin抑制剂BC2059作为单一疗法以及与蛋白酶体抑制剂结合的体内和体外的理论依据。在这里，我们显示了人类骨髓瘤细胞系（HMCL）中β-catenin的核定位，与经典Wnt途径的激活一致。BC2059减弱细胞质和细胞核中β-catenin的水平，降低TCF4 / LEF复合物的转录活性及其靶基因毒素2的表达。用BC2059处理HMCL以剂量依赖性方式抑制增殖并诱导凋亡。在HMCL-基质细胞共培养物中也观察到了这一点，从而减轻了基质提供的保护作用。同样，BC2059在体外可诱导原发性多发性骨髓瘤样品中的细胞凋亡，从而在健康的外周血单核细胞上产生最小的细胞凋亡。此外，它在HMCL和原发性多发性骨髓瘤样品中均与蛋白酶体抑制剂硼替佐米协同作用。最后，在人类骨髓瘤病的异种移植模型中，BC2059会延迟肿瘤的生长并延长生存期，并具有轻微的靶向副作用。总的来说，这些结果证明了在临床上可达到的剂量下，在体外和体内用BC2059靶向Wnt /β-catenin途径的功效。这些发现支持BC2059用于治疗多发性骨髓瘤的进一步临床评估。分子癌疗法；16（9）; 1765–78。©2017 AACR。