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

• 批准号: 10826323
• 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
• 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/10826323
• 关键词: Adolescent and Young Adult; Antisense Oligonucleotides; Catalytic Domain; Cells; Child; Cyclic AMP-Dependent Protein Kinases; DNA; Fibrolamellar Hepatocellular Carcinoma; Fusion Oncogene Proteins; Genes; Heat-Shock Response; Human; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Messenger RNA; Molecular Chaperones; Mus; Neoplasm Metastasis; Oncoproteins; Operative Surgical Procedures; Organoids; PRKACA gene; Pathogenesis; Pathology; Pediatric Neoplasm; Primary Neoplasm; Proteins; Therapeutic; Tissues; Transcript; fusion gene; human genome sequencing; multicatalytic endopeptidase complex; small hairpin RNA; small molecule; therapeutic target; tumor

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. The first two projects will explore the pathogenesis: In project 1, what is different about the fusion oncoprotein that causes changes in the cell; In Project 2, how its expression in human organoids or in mouse tissue leads to a specific pathology in the liver. The next two projects will explore the therapeutics: In project 3 targeting to the fusion mRNA transcript with shRNA and anti-sense oligonucleotides and in Project 4, targeting the fusion oncoprotein through small molecules to block activity, or small molecules to send it to the proteasome, or small molecules for allosteric inhibition. Page 98 Project Summary/Abstract

项目摘要 /摘要 纤维状肝细胞癌（FLC）是儿童，青少年和 年轻人。原发性肿瘤是由DNA中的单个变化引发和驱动的：删除〜400Kb 这导致热激伴侣DNAJB1与蛋白质催化亚基之间的融合基因 激酶A，prkaca。如果肿瘤仅限于肝脏，则手术是接受的治疗。但是，如果是 肿瘤已经转移，没有接受的治疗。该项目将确定融合量蛋白如何 导致发病机理，并将发展针对融合癌蛋白的治疗剂。前两个项目 将探索发病机理：在项目1中，导致变化的融合癌蛋白有什么不同 在细胞中；在项目2中，其在人类器官或小鼠组织中的表达如何导致特定的病理 在肝脏中。接下来的两个项目将探讨治疗学：在项目3中，针对融合mRNA 带有shRNA和抗敏感性寡核苷酸的转录本，在项目4中，靶向融合癌蛋白 通过小分子阻止活性或小分子将其发送到蛋白酶体或小分子 用于变构抑制。 第98页 项目摘要/摘要