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: 10630303
• 负责人: Siobhan Malany
• 金额: $ 20.96万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630303
• 关键词: Adverse effects; Adverse event; Apoptosis; Automobile Driving; BAY 54-9085; Biological; Biological Assay; Biological Availability; 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; Inhibition of Cell Proliferation; Invaded; 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; Proliferating; 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; 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.

项目总结/摘要 索拉非尼（Nexavar®）是第一个FDA批准的晚期肝细胞癌靶向药物 肝癌（HCC）患者和一线治疗。然而，它只提供了一个适度的生活 由于低缓解率，约40%的晚期不可切除HCC患者的严重 不良事件和获得性耐药。一些与HCC相关的细胞通路 发展和不良预后也导致对索拉非尼的耐药性。了解哪些 通过提供HCC特异性临床生物标志物， 以及新的治疗靶点的开发。其中一条通路在50%的HCC中失调 是Wnt/β-连环蛋白的激活，由激酶级联反应诱导，特别是Ras/Raf/Mek/Erk （索拉非尼靶向）、PI 3 K/AKT/TOR和p38 MAPK导致GSK-3β激酶失活。 β-catenin逃避GSK-3β的磷酸化和蛋白酶体降解后， 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抑制的抗凋亡、细胞增殖、血管生成 急救和入侵。我们提出的一种新的对抗索拉非尼耐药性的策略包括： 抑制趋化因子受体CXCR 6的过度活化。来自CXCR 6及其配体的信号传导 CXCL 16通过下游激酶驱动对索拉非尼的耐药性，并在Ser-9达到顶峰 磷酸-GSK 3 β/β-连环蛋白激活。SK-Hep-1和其他肝癌细胞中CXCR 6的敲低 与p38活性降低、GSK 3 β活性增加、细胞膜螯合有关。 β-catenin和β-catenin在细胞核中转录活性的下调。我们有 开发了一流的小分子铅，SBI-457，拮抗CXCR 6受体， 在小鼠中可口服生物利用，并在30天小鼠中有效减弱肿瘤生长 用于晚期HCC的异种移植物模型，没有副作用。由于CXCR 6/CXCL 16不是高度 SBI-457在非癌性肝细胞和其他肝组织中表达，但在 在高剂量和慢性暴露下。由于没有已知的临床CXCR 6拮抗剂 到目前为止，在晚期肝细胞癌中，将先导SBI-457作为单一药剂进行优化，将是第一个具有创新意义的 我们的应用方面。第二项重大创新是优化的CXCR 6 索拉非尼拮抗剂在耐药HCC细胞中的作用，以了解并克服主要的 耐药性的瓶颈。因此，小分子CXCR 6拮抗剂在这一领域得到了发展。 应用有可能扩大索拉非尼和其他靶向药物的临床应用 通过再致敏、改善反应和降低剂量，从而降低毒性， 不良事件的风险。