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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

基本信息

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
项目类别：
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

项目摘要

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/文摘