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Targeting the oncoprotein that drives FLC

靶向驱动 FLC 的癌蛋白

基本信息

批准号：
10902751
负责人：
SANFORD M SIMON
金额：
$ 18.88万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10902751
关键词：
Adolescent and Young Adult Affinity Binding Biological Assay Catalytic Domain Cell Survival Cells Cyclic AMP-Dependent Protein Kinases DNA Dissociation Fibrolamellar Hepatocellular Carcinoma Fusion Oncogene Proteins Genetically Engineered Mouse Goals Heat-Shock Response Holoenzymes Human Lead Libraries Liver Malignant Epithelial Cell Modeling Modification Molecular Molecular Chaperones Mus Myristic Acids National Center for Advancing Translational Sciences Neoplasm Metastasis Oncogenic Oncoproteins Operative Surgical Procedures Organoids PRKACA gene Pediatric Neoplasm Peptides Pharmaceutical Chemistry Phosphotransferases Pre-Clinical Model Primary Neoplasm Process Protac Protein-Serine-Threonine Kinases Proteins Scanning Specificity Testing Therapeutic Therapeutic Index Therapeutic Uses Ubiquitination United States National Institutes of Health X-Ray Crystallography candidate selection design efficacy testing fusion gene high throughput screening improved in vivo inhibitor molecular dynamics multicatalytic endopeptidase complex patient derived xenograft model screening small molecule therapeutic target tumor tumor growth ubiquitin-protein ligase

项目摘要

Project Summary / Abstract Fibrolamellar hepatocellular carcinoma (FLC) is a usually lethal primary tumor in children, adolescents and young adults. The primary tumor is initiated and driven by a single alteration in the DNA: A deletion of ~400kb that results in a fusion gene between the heat shock co-chaperone DNAJB1 and the catalytic subunit of protein kinase A, PRKACA. If the tumor is limited to the liver, then surgery is the accepted therapy. However, if the tumor has metastasized, there is no accepted therapy. Project 4 will develop therapeutics targeted to the fusion oncoprotein. It will use therapeutics to block the kinase activity of the oncoprotein and therapeutics to target the oncoprotein to the proteasome for destruction. The therapeutics will be tested on isolated protein, in dissociated cells from patient-derived xenografts, in human liver organoids of FLC and in mice with patient derived xenografts and in genetically engineered mouse models.

项目总结/摘要纤维板层型肝细胞癌（FLC）是儿童、青少年和老年人常见的致死性原发性肿瘤。年轻人原发性肿瘤由DNA中的单一改变引发和驱动：约400 kb的缺失导致热休克辅助分子伴侣DNAJB 1和蛋白质催化亚基之间的融合基因激酶A，PRKACA。如果肿瘤局限于肝脏，那么手术是公认的治疗方法。但如果肿瘤已经转移，没有公认的治疗方法。项目4将开发针对融合癌蛋白它将使用治疗剂来阻断癌蛋白的激酶活性，将癌蛋白靶向蛋白酶体进行破坏。该疗法将在分离的蛋白质上进行测试，来自患者来源的异种移植物的解离细胞，在FLC的人肝类器官和患有患者的小鼠中衍生的异种移植物和基因工程小鼠模型。