The Center for Synovial Sarcoma Biology and Therapeutics

滑膜肉瘤生物学和治疗中心

基本信息

批准号：
10797558
负责人：
Cigall Kadoch
金额：
$ 20万
依托单位：
DANA-FARBER CANCER INST
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：
2023-04-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10797558
关键词：
3-Dimensional ATP phosphohydrolase Administrative Supplement Antibodies Architecture Area Award BMI1 gene Binding Binding Proteins Biological Biological Assay Biological Models Biology Budgets CRISPR/Cas technology Cell Line Cell model ChIP-seq Chemicals Childhood Chromatin Chromatin Remodeling Factor Clinical Collaborations Complex Computer Analysis Cryoelectron Microscopy DNA Data Data Collection Development Disease EWS-FLI1 fusion protein Equilibrium Funding Fusion Oncogene Proteins Future Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting Genes Genetic Genetic study Genomics Goals Histones Human Institution Knowledge Laboratories Lesion Link Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Manuscripts Methods Mission Molecular Mutate Mutation Nature Nucleosomes Oncogenic PRC1 Protein Parents Pathway interactions Preparation Process Productivity Protein Biochemistry Proteins Regulation Research Research Project Grants Role Running Series Site Structure Testing Therapeutic Time Work cancer type combat cost experimental study falls fitness genome-wide genomic profiles histone modification inhibitor interdisciplinary approach lethal factor meetings member multidisciplinary novel novel therapeutic intervention novel therapeutics permissiveness programs protein complex screening soft tissue spatiotemporal structural biology synovial sarcoma targeted treatment therapeutic development therapeutic target three dimensional structure

项目摘要

Project Summary/Abstract This section is unchanged from the U54 CA231638 parent award. The overarching goal of this FusOnC2 Center for Synovial Sarcoma Biology and Therapeutics is to develop and execute a comprehensive, multidisciplinary set of approaches rooted in protein biochemistry and structural biology to define the mechanistic underpinnings of synovial sarcoma and unmask opportunities for therapeutic development. This Center’s mission is tightly aligned with that of the larger Consortium on Fusion Oncoproteins in Childhood Cancers as well as the goals of the Beau Biden Cancer Moonshot Initiative. Indeed, owing in part to our group’s recent findings surrounding the discovery of SS18-SSX as a stable and integrated member of the mammalian SWI/SNF (BAF) chromatin remodeling complex, a major impetus for the development of this Consortium has been the growing knowledge that pediatric fusion oncoproteins that are pathognomonic for specific cancer types often function via disruption of the structure and/or activity of protein complexes that govern chromatin architecture and hence gene control. We have shown that at least two of the fusion oncoproteins highlighted as major areas of emphasis within the Consortium, SS18-SSX and EWS-FLI1, act specifically through BAF complexes to drive their cancer-specific oncogenic gene expression patterns. Study of multimeric BAF complexes and their functions, structure, and interactions are further suggested by genetic studies across human cancer types which have indicated that among all chromatin remodeling complexes, genes encoding mSWI/SNF complex subunits are among the most frequently mutated, at over 20% of all human cancers. Here we present a multi-institutional, highly collaborative and multidisciplinary approach to comprehensively interrogate biologic mechanisms underpinning the function of the SS18-SSX oncogenic fusion in synovial sarcoma and to use each of these approaches and the results generated to launch targeted therapeutic discovery campaigns that are directly linked to the mechanisms identified. Specifically, our approach encompasses three major areas: (1) BAF complex targeting, gene regulation, and chromatin state; (2) Understanding the role of the wild-type SS18 protein in the context of the SS18-SSX fusion, its protein-level regulation, and mechanisms by which its stabilization can be exploited for therapeutic benefit; (3) Using genome-scale genetic perturbation strategies to discover and mechanistically characterize SS-specific vulnerabilities, especially those in chromatin-bound protein complexes and related pathways. As a Center, the unique expertise of each PI and the highly integrative nature of the research projects, cores, and collaborators provide the strongest possible likelihood that the aims will be successfully achieved and that novel therapeutic strategies will emerge from this Center. Project Summary/Abstract Page 69

项目概要/摘要此部分与 U54 CA231638 家长奖相同。 FusOnC2 滑膜肉瘤生物学和治疗中心的总体目标是开发并执行一套全面的、多学科的方法，植根于蛋白质生物化学和结构生物学来定义滑膜肉瘤的机制基础并揭示滑膜肉瘤的机会该中心的治疗使命与更大的融合联盟的使命紧密结合。儿童癌症中的癌蛋白以及博拜登癌症登月计划的目标确实如此。部分原因是我们小组最近发现 SS18-SSX 作为稳定且集成的哺乳动物 SWI/SNF (BAF) 染色质重塑复合体的成员，是该联盟的发展是因为人们越来越认识到儿科融合癌蛋白通常通过结构和/或活性的功能破坏来识别特定癌症类型控制染色质结构以及基因控制的蛋白质复合物至少已经证明了这一点。两个融合癌蛋白被强调为联盟内的主要重点领域，SS18-SSX 和 EWS-FLI1，通过 BAF 复合物特异性发挥作用，驱动其癌症特异性致癌基因多聚 BAF 复合物及其功能、结构和相互作用的研究跨人类癌症类型的遗传学研究进一步表明，在所有癌症类型中染色质重塑复合体、编码 mSWI/SNF 复合体亚基的基因是其中最重要的经常发生突变，占所有人类癌症的 20% 以上。在这里，我们提出了一种多机构、高度协作和多学科的方法来全面探究滑膜中 SS18-SSX 致癌融合功能的生物学机制肉瘤并使用这些方法和产生的结果来启动靶向治疗发现活动与所确定的机制直接相关，特别是我们的方法。涵盖三个主要领域：(1) BAF 复合物靶向、基因调控和染色质状态；(2) 了解野生型 SS18 蛋白在 SS18-SSX 融合中的作用及其蛋白水平调节以及利用其稳定作用获得治疗益处的机制；基因组规模的遗传扰动策略来发现和机械地表征 SS 特异性脆弱性，特别是染色质结合蛋白复合物和相关途径中的脆弱性。每个 PI 的独特专业知识以及研究项目、核心和研究的高度综合性合作者提供了成功实现目标的最大可能性，并且该中心将出现新的治疗策略。项目总结/摘要第 69 页