Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Prev Res (Phila). 2023 Jan 4;16(1):17-28. doi: 10.1158/1940-6207.CAPR-22-0332.
We evaluated the cancer preventive efficacy of TAK-242, an inhibitor of Toll-like receptor 4 (TLR4), in a mouse model of hepatocellular carcinoma (HCC) occurring in the context of nonalcoholic steatohepatitis (NASH). We also assessed the cellular events associated with the preventive treatment efficacy. We tested oral administration of TAK-242, at clinically relevant but toxicity-reducing doses and scheduling, in mice with hepatocyte-specific deletion of Pten (HepPten-). The optimal dose and oral gavage formulation of TAK-242 were determined to be 30 mg/kg in 5% DMSO in 30% 2-hydroxypropyl-β-cyclodextrin. Daily oral administration of 30 mg/kg TAK-242 over 18 weeks was well tolerated and resulted in reduced development of tumors (lesions > 7.5 mm3) in HepPten- mice. This effect was accompanied by reduced macrovesicular steatosis and serum levels of alanine aminotransferase. In addition, 30 mg/kg TAK-242 daily treatment of small preexisting adenomas (lesions < 7.5 mm3) over 18 weeks, significantly reduced their progression to HCC. RNA sequencing identified 220 hepatic genes significantly altered upon TAK-242 treatment, that significantly correlated with tumor burden. Finally, cell deconvolution analysis revealed that TAK-242 treatment resulted in reduced hepatic populations of endothelial cells and myeloid-derived immune cells (Kupffer cells, Siglec-H high dendritic cells, and neutrophilic granule protein high neutrophils), while the proportion of mt-Nd4 high hepatocytes significantly increased, suggesting a decrease in hepatic inflammation and concomitant increase in mitochondrial function and oxidative phosphorylation upon TLR4 inhibition. In conclusion, this study identified treatment strategies and novel molecular and cellular mechanisms associated with the prevention of HCC in the context of NASH that merit further investigations.
Means to prevent development of HCC or progression of small adenomas to HCC in patients with NASH are urgently needed to reduce the growing mortality due to HCC. We characterized the chemopreventive effect of oral administration of the TLR4 inhibitor TAK-242 in a model of NASH-associated HCC.
评估 Toll 样受体 4（TLR4）抑制剂 TAK-242 在非酒精性脂肪性肝炎（NASH）背景下发生的肝细胞癌（HCC）小鼠模型中的抗癌预防效果。我们还评估了与预防治疗效果相关的细胞事件。我们在具有肝细胞特异性缺失 Pten（HepPten-）的小鼠中测试了 TAK-242 的口服给药，采用临床相关但降低毒性的剂量和方案。确定 TAK-242 的最佳剂量和口服管饲配方为 30mg/kg，在 5%二甲基亚砜中，在 30% 2-羟丙基-β-环糊精中。18 周内每天口服 30mg/kg TAK-242 可耐受良好，并可减少 HepPten-小鼠肿瘤（病变>7.5mm3）的发生。这种效果伴随着大泡性脂肪变性和丙氨酸氨基转移酶血清水平的降低。此外，18 周内每天用 30mg/kg TAK-242 治疗小的前腺肿瘤（病变<7.5mm3），显著减少了它们向 HCC 的进展。RNA 测序确定了 TAK-242 治疗后肝脏基因显著改变的 220 个基因，这些基因与肿瘤负担显著相关。最后，细胞去卷积分析表明，TAK-242 治疗导致肝内皮细胞和髓样来源的免疫细胞（Kupffer 细胞、Siglec-H 高树突状细胞和中性粒细胞颗粒蛋白高中性粒细胞）的数量减少，而 mt-Nd4 高肝细胞的比例显著增加，表明肝内炎症减少，同时线粒体功能和氧化磷酸化增加，提示 TLR4 抑制后。总之，本研究确定了 NASH 背景下 HCC 预防的治疗策略和与 HCC 预防相关的新的分子和细胞机制，值得进一步研究。
迫切需要预防 NASH 患者 HCC 的发展或小腺瘤进展为 HCC 的方法，以降低因 HCC 导致的死亡率不断上升。我们描述了 TLR4 抑制剂 TAK-242 在 NASH 相关 HCC 模型中的化学预防作用。
