Department of Cancer Immunology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Ullernschausseen 70, 0379, Montebello, Oslo, Norway.
KG Jebsen Centre for B Cell Malignancies, Faculty of Medicine, University of Oslo, Oslo, Norway.
Sci Rep. 2021 Mar 18;11(1):6317. doi: 10.1038/s41598-021-85613-8.
Chemo-immunotherapy has improved survival in B-cell lymphoma patients, but refractory/relapsed diseases still represent a major challenge, urging for development of new therapeutics. Karonudib (TH1579) was developed to inhibit MTH1, an enzyme preventing oxidized dNTP-incorporation in DNA. MTH1 is highly upregulated in tumor biopsies from patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, hence confirming a rationale for targeting MTH1. Here, we tested the efficacy of karonudib in vitro and in preclinical B-cell lymphoma models. Using a range of B-cell lymphoma cell lines, karonudib strongly reduced viability at concentrations well tolerated by activated normal B cells. In B-cell lymphoma cells, karonudib increased incorporation of 8-oxo-dGTP into DNA, and prominently induced prometaphase arrest and apoptosis due to failure in spindle assembly. MTH1 knockout cell lines were less sensitive to karonudib-induced apoptosis, but were displaying cell cycle arrest phenotype similar to the wild type cells, indicating a dual inhibitory role of the drug. Karonudib was highly potent as single agent in two different lymphoma xenograft models, including an ABC DLBCL patient derived xenograft, leading to prolonged survival and fully controlled tumor growth. Together, our preclinical findings provide a rationale for further clinical testing of karonudib in B-cell lymphoma.
化疗免疫疗法改善了 B 细胞淋巴瘤患者的生存率，但难治/复发疾病仍然是一个主要挑战，迫切需要开发新的治疗方法。Karonudib（TH1579）的开发旨在抑制 MTH1，一种防止氧化 dNTP 掺入 DNA 的酶。MTH1 在弥漫性大 B 细胞淋巴瘤（DLBCL）和伯基特淋巴瘤患者的肿瘤活检中高度上调，因此证实了针对 MTH1 的合理依据。在这里，我们在体外和临床前 B 细胞淋巴瘤模型中测试了 karonudib 的疗效。使用一系列 B 细胞淋巴瘤细胞系，karonudib 在激活的正常 B 细胞可耐受的浓度下强烈降低了细胞活力。在 B 细胞淋巴瘤细胞中，karonudib 增加了 8-oxo-dGTP 掺入 DNA 的量，并由于纺锤体组装失败而显著诱导早前期阻滞和凋亡。MTH1 敲除细胞系对 karonudib 诱导的凋亡的敏感性较低，但表现出与野生型细胞相似的细胞周期阻滞表型，表明该药物具有双重抑制作用。Karonudib 作为单一药物在两种不同的淋巴瘤异种移植模型中具有很高的活性，包括 ABC DLBCL 患者来源的异种移植，导致延长的生存时间和完全控制肿瘤生长。总之，我们的临床前研究结果为进一步在 B 细胞淋巴瘤中测试 karonudib 提供了依据。
