Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Clin Cancer Res. 2012 Sep 1;18(17):4669-81. doi: 10.1158/1078-0432.CCR-12-0779. Epub 2012 Jul 17.
NF-κB transcription factor plays a key role in the pathogenesis of multiple myeloma in the context of the bone marrow microenvironment. Both canonical and noncanonical pathways contribute to total NF-κB activity. Recent studies have shown a critical role for the noncanonical pathway: selective inhibitors of the canonical pathway present a limited activity, mutations of the noncanonical pathway are frequent, and bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity.
Multiple myeloma cell lines, primary patient cells, and the human multiple myeloma xenograft murine model were used to examine the biologic impact of dual inhibition of both canonical and noncanonical NF-κB pathways.
We show that PBS-1086 induces potent cytotoxicity in multiple myeloma cells but not in peripheral blood mononuclear cells. PBS-1086 overcomes the proliferative and antiapoptotic effects of the bone marrow milieu, associated with inhibition of NF-κB activity. Moreover, PBS-1086 strongly enhances the cytotoxicity of bortezomib in bortezomib-resistant multiple myeloma cell lines and patient multiple myeloma cells. PBS-1086 also inhibits osteoclastogenesis through an inhibition of RANK ligand (RANKL)-induced NF-κB activation. Finally, in a xenograft model of human multiple myeloma in the bone marrow milieu, PBS-1086 shows significant in vivo anti-multiple myeloma activity and prolongs host survival, associated with apoptosis and inhibition of both NF-κB pathways in tumor cells.
Our data show that PBS-1086 is a promising dual inhibitor of the canonical and noncanonical NF-κB pathways. Our preclinical study therefore provides the framework for clinical evaluation of PBS-1086 in combination with bortezomib for the treatment of multiple myeloma and related bone lesions.
NF-κB 转录因子在骨髓微环境中的多发性骨髓瘤发病机制中起着关键作用。经典途径和非经典途径都有助于 NF-κB 活性的总和。最近的研究表明非经典途径起着至关重要的作用：经典途径的选择性抑制剂活性有限，非经典途径的突变频繁，硼替佐米诱导的细胞毒性不能完全归因于对经典 NF-κB 活性的抑制。
使用多发性骨髓瘤细胞系、原代患者细胞和人多发性骨髓瘤异种移植鼠模型来研究双重抑制经典和非经典 NF-κB 途径的生物学影响。
我们表明 PBS-1086 可在多发性骨髓瘤细胞中诱导强烈的细胞毒性，但在外周血单核细胞中则没有。PBS-1086 克服了骨髓环境中的增殖和抗凋亡作用，与 NF-κB 活性的抑制有关。此外，PBS-1086 可显著增强硼替佐米在硼替佐米耐药多发性骨髓瘤细胞系和患者多发性骨髓瘤细胞中的细胞毒性。PBS-1086 还通过抑制 RANK 配体（RANKL）诱导的 NF-κB 激活来抑制破骨细胞生成。最后，在骨髓环境中的人多发性骨髓瘤异种移植模型中，PBS-1086 显示出显著的体内抗多发性骨髓瘤活性，并延长了宿主的存活时间，与肿瘤细胞中的细胞凋亡和 NF-κB 途径的抑制有关。
我们的数据表明，PBS-1086 是经典和非经典 NF-κB 途径的有前途的双重抑制剂。因此，我们的临床前研究为评估 PBS-1086 与硼替佐米联合治疗多发性骨髓瘤和相关骨病变的临床评价提供了框架。
