Preclinical development of CXCR6 antagonists to target sorafenib resistance in Hepatocellular Carcinoma

针对肝细胞癌索拉非尼耐药性的 CXCR6 拮抗剂的临床前开发

• 批准号: 10435160
• 负责人: Siobhan Malany
• 金额: $ 17.82万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-27 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435160
• 关键词: Adverse effects; Adverse event; Apoptosis; Attenuated; Automobile Driving; BAY 54-9085; Biological; Biological Assay; Biological Markers; CXCR6 gene; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Chemical Structure; Chemoresistance; Chronic; Clinical; Cyclin D1; Development; Dose; Down-Regulation; Drug Kinetics; Drug Targeting; Drug resistance; FDA approved; Genetic Transcription; Growth; Growth Factor Receptors; Hepatocyte; Human; Inflammation; Lead; Life Extension; Ligands; Liver; MAP Kinase Gene; MCL1 gene; MEKs; Malignant Epithelial Cell; Malignant neoplasm of liver; Measures; Mediating; Membrane; Molecular; Molecular Bank; Mus; Neoplasm Metastasis; Nexavar; Nuclear; Nuclear Translocation; Oncogenic; Oral; PI3K/AKT; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphotransferases; Primary carcinoma of the liver cells; Prognosis; Property; Proteins; Ras/Raf; Resistance; Serious Adverse Event; Signal Transduction; Structure-Activity Relationship; Tissues; Toxic effect; Tyrosine Kinase Inhibitor; United States National Institutes of Health; Unresectable; Vascular Endothelial Growth Factors; Xenograft Model; adverse event risk; angiogenesis; antagonist; base; beta catenin; beta-arrestin; c-myc Genes; chemokine receptor; clinical biomarkers; clinically relevant; design; glycogen synthase kinase 3 beta; hepatocellular carcinoma cell line; hepatoma cell; high throughput screening; human model; immune checkpoint blockers; improved; in vivo; individualized medicine; innovation; knock-down; lead optimization; neoplastic cell; new therapeutic target; novel; novel strategies; overexpression; p38 Mitogen Activated Protein Kinase; patient response; preclinical development; preclinical evaluation; programs; receptor; recruit; repository; response; response biomarker; screening; small molecule; small molecule inhibitor; specific biomarkers; success; survivin; targeted agent; tumor growth; tumor progression

PROJECT SUMMARY/ABSTRACT Sorafenib (Nexavar®) is the first FDA approved targeted drug for advanced hepatocellular carcinoma (HCC) patients and a first-line treatment. However, it offers only a moderate life extension in about 40% of advanced unresectable HCC patients due to low response rate, serious adverse events and acquired resistance. Some of the cellular pathways associated with HCC development and poor prognosis also cause resistance to sorafenib. Understanding which pathway will have monumental impact by providing HCC specific clinical biomarkers of response and the development of new therapeutic targets. One such pathway dysregulated in 50% of HCCs is the activation of Wnt/β-catenin, induced by kinase cascades, notably the Ras/Raf/Mek/Erk (targeted by sorafenib), PI3K/AKT/TOR and p38 MAPK leading to inactivation of GSK-3β kinase. Post its escape from phosphorylation by GSK-3β and proteasomal degradation, β-catenin accumulates in the nucleus and activates transcription of several oncogenic proteins rendering sorafenib ineffective and promotes unchecked anti-apoptosis, cell proliferation, angiogenesis, EMT and invasion. A novel strategy proposed by us for combating resistance to sorafenib involves inhibiting hyperactivation of a chemokine receptor CXCR6. Signaling from CXCR6 and its ligand CXCL16 drives resistance to sorafenib through the downstream kinases and culminates at Ser-9 phospho-GSK3β/β-catenin activation. CXCR6-knockdown in SK-Hep-1 and other hepatoma cell lines is correlated with lower p38 activity, increased GSK3β activity, membrane sequestration of β-catenin and downregulation of β-catenin transcriptional activity in the nucleus. We have developed a first-in-class small molecule lead, SBI-457, that antagonizes the CXCR6 receptor, is orally bioavailable in mice and efficacious at attenuating tumor growth in a 30-day mouse xenograft model for advanced HCC with no adverse effects. Since CXCR6/CXCL16 are not highly expressed in non-cancerous hepatocyte and other liver tissue, SBI-457 is expectedly non-toxic in vivo under high dose and chronic exposure. Since there are no known clinical CXCR6 antagonists to date, optimization of lead SBI-457 as a single agent in advanced HCC will be the first innovative aspect of our application. A second major innovation is a combination of optimized CXCR6 antagonists with sorafenib in resistant HCC cells to understand and then overcome the major bottleneck of chemoresistance. Hence small molecule CXCR6 antagonist leads developed in this application have the potentially to expand the clinical use of sorafenib and other targeted agents by re-sensitization, improved response, and lowering of the dose thereby reducing toxicity and risk of adverse events.

项目概要/摘要 索拉非尼 (Nexavar®) 是 FDA 批准的第一个治疗晚期肝细胞癌的靶向药物 癌症（HCC）患者和一线治疗。然而，它只提供适度的生活 由于反应率低，大约 40% 的晚期不可切除的 HCC 患者会进行延伸，严重的 不良事件和获得性耐药性。一些与 HCC 相关的细胞通路 发育和不良预后也会导致对索拉非尼的耐药。了解哪些 通过提供 HCC 特异性临床反应生物标志物，途径将产生巨大影响 以及新治疗靶点的开发。 50% 的 HCC 中存在这样一种通路失调 是 Wnt/β-连环蛋白的激活，由激酶级联诱导，特别是 Ras/Raf/Mek/Erk （索拉非尼靶向）、PI3K/AKT/TOR 和 p38 MAPK 导致 GSK-3β 激酶失活。 逃脱 GSK-3β 磷酸化和蛋白酶体降解后，β-连环蛋白 在细胞核中积累并激活几种致癌蛋白的转录 索拉非尼无效并促进不受控制的抗凋亡、细胞增殖、血管生成、 EMT 和入侵。我们提出的一种对抗索拉非尼耐药性的新策略涉及 抑制趋化因子受体 CXCR6 的过度激活。来自 CXCR6 及其配体的信号传导 CXCL16 通过下游激酶驱动对索拉非尼的耐药性并在 Ser-9 处达到顶峰 磷酸-GSK3β/β-连环蛋白激活。 SK-Hep-1 和其他肝癌细胞中的 CXCR6 敲低 细胞系与较低的 p38 活性、增加的 GSK3β 活性、膜隔离相关 β-连环蛋白和细胞核内β-连环蛋白转录活性的下调。我们有 开发了一种一流的小分子先导化合物 SBI-457，它可以拮抗 CXCR6 受体， 小鼠口服生物利用度高，可有效抑制 30 天小鼠的肿瘤生长 用于晚期 HCC 的异种移植模型，无副作用。由于CXCR6/CXCL16不高 SBI-457 在非癌性肝细胞和其他肝组织中表达，预计在 高剂量和长期暴露下的体内。由于临床上尚无已知的 CXCR6 拮抗剂 迄今为止，将先导 SBI-457 作为单一药物治疗晚期 HCC 的优化将是第一个创新 我们应用程序的一个方面。第二个主要创新是优化的 CXCR6 的组合 索拉非尼拮抗剂在耐药性 HCC 细胞中的作用，以了解并克服主要的 化疗耐药的瓶颈。因此，本研究开发了小分子 CXCR6 拮抗剂先导化合物 应用有可能扩大索拉非尼和其他靶向药物的临床应用 通过重新敏化、改善反应和降低剂量，从而降低毒性和 不良事件的风险。