Center for therapeutic targeting of the Fusion Oncoprotein of Fibrolamellar Hepatocellular Carcinoma

纤维板层肝细胞癌融合癌蛋白治疗靶向中心

基本信息

批准号：
10221308
负责人：
SANFORD M SIMON
金额：
$ 18.91万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221308
关键词：
Adolescent and Young Adult Affect Age Antisense Oligonucleotides Belief Benchmarking Biocompatible Materials Biological Models Catalytic Domain Cells Child Chimeric Proteins Communities Cyclic AMP-Dependent Protein Kinases DNA Failure Fibrolamellar Hepatocellular Carcinoma Fusion Oncogene Proteins Genes Genetic Genome Goals Heat-Shock Response Human Individual Liver Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of liver Messenger RNA Molecular Chaperones Neoplasm Metastasis Oncoproteins Operative Surgical Procedures Organ PRKACA gene Pathogenesis Patients Pediatric Neoplasm Population Primary Neoplasm Proteins Proteome Research Personnel Somatic Mutation Testing Therapeutic Transcript Work combat design fusion gene human genome sequencing knock-down multicatalytic endopeptidase complex patient population small molecule targeted treatment therapeutic development therapeutic evaluation therapeutic target transcriptome tumor

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. This project will determine how the fusion oncoprotein leads to pathogenesis and will develop therapeutics targeted to the fusion oncoprotein. Pathogenesis is being probed by examining what is different about the fusion oncoprotein that causes changes in the cell. Therapeutics will target the fusion oncoprotein through small molecules to block activity, or small molecules to send it to the proteasome, or small molecules for allosteric inhibition.

项目概要/摘要纤维板层肝细胞癌（FLC）是儿童、青少年和年轻人中通常致命的原发性肿瘤。原发性肿瘤是由 DNA 中的单个改变引发和驱动的：约 400kb 的缺失导致热休克共伴侣 DNAJB1 和蛋白激酶 A 催化亚基 PRKACA 之间产生融合基因。如果肿瘤仅限于肝脏，则手术是公认的治疗方法。然而，如果肿瘤已经转移，则没有公认的治疗方法。该项目将确定融合癌蛋白如何导致发病机制，并将开发针对融合癌蛋白的治疗方法。通过检查引起细胞变化的融合癌蛋白的不同之处来探究发病机制。治疗方法将通过小分子靶向融合癌蛋白以阻断活性，或通过小分子将其发送至蛋白酶体，或通过小分子进行变构抑制。