Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey.
ImmuneTarget Inc., San Diego, California.
Mol Cancer Ther. 2022 Dec 2;21(12):1798-1809. doi: 10.1158/1535-7163.MCT-22-0257.
Multiple myeloma is a plasma cell malignancy that is still largely incurable, despite considerable progress in recent years. NF-κB is a well-established therapeutic target in multiple myeloma, but none of the currently available treatment options offer direct, specific pharmacologic targeting of NF-κB transcriptional activity. Thus, we designed a novel direct NF-κB inhibitor (IT848) as a drug candidate with strong potential for clinical translation and conducted comprehensive in vitro and in vivo mechanistic studies in multiple myeloma cell lines, primary multiple myeloma cells, xenograft models, and immunocompetent mouse models of multiple myeloma. Here, we show that IT848 inhibits NF-κB activity through inhibition of DNA binding of all five NF-κB subunits. IT848 treatment of multiple myeloma cell lines and patient samples inhibited proliferation and induced caspase-dependent and independent apoptosis. In addition to direct NF-κB inhibitory effects, IT848 treatment altered the redox homeostasis of multiple myeloma cells through depletion of the reduced glutathione pool, selectively inducing oxidative stress in multiple myeloma but not in healthy cells. Multiple myeloma xenograft studies confirmed the efficacy of IT848 as single agent and in combination with bortezomib. Furthermore, IT848 significantly improved survival when combined with programmed death protein 1 inhibition, and correlative immune studies revealed that this clinical benefit was associated with suppression of regulatory T-cell infiltration of the bone marrow microenvironment. In conclusion, IT848 is a potent direct NF-κB inhibitor and inducer of oxidative stress specifically in tumor cells, displaying significant activity against multiple myeloma cells in vitro and in vivo, both as monotherapy as well as in combination with bortezomib or immune checkpoint blockade.
多发性骨髓瘤是一种浆细胞恶性肿瘤，尽管近年来取得了相当大的进展，但仍基本上无法治愈。NF-κB 是多发性骨髓瘤的一个成熟的治疗靶点，但目前可用的治疗方法均不能直接、特异性地靶向 NF-κB 转录活性。因此，我们设计了一种新型的直接 NF-κB 抑制剂（IT848）作为具有很强临床转化潜力的候选药物，并在多发性骨髓瘤细胞系、原代多发性骨髓瘤细胞、异种移植模型和多发性骨髓瘤免疫功能正常的小鼠模型中进行了全面的体外和体内机制研究。在这里，我们证明 IT848 通过抑制所有五个 NF-κB 亚基的 DNA 结合来抑制 NF-κB 活性。IT848 处理多发性骨髓瘤细胞系和患者样本可抑制增殖并诱导半胱天冬酶依赖性和非依赖性细胞凋亡。除了直接的 NF-κB 抑制作用外，IT848 处理通过耗尽还原型谷胱甘肽池来改变多发性骨髓瘤细胞的氧化还原稳态，选择性地诱导多发性骨髓瘤中的氧化应激，而不是在健康细胞中诱导。多发性骨髓瘤异种移植研究证实了 IT848 作为单一药物以及与硼替佐米联合使用的疗效。此外，当与程序性死亡蛋白 1 抑制联合使用时，IT848 显著提高了存活率，相关免疫研究表明，这种临床获益与抑制调节性 T 细胞浸润骨髓微环境有关。总之，IT848 是一种有效的直接 NF-κB 抑制剂和肿瘤细胞中氧化应激的诱导剂，在体外和体内对多发性骨髓瘤细胞均具有显著的活性，无论是单独使用还是与硼替佐米或免疫检查点阻断联合使用。
