Targeting SS18-SSX biology in synovial sarcomagenesis

总体：项目总结/摘要(家长奖) 此应用程序响应RFA-CA-17-049，建议建立一个分布在 三个拥有实验室的机构都专注于SS18-SSX(以前称为SYT-SSX)融合的生物学 致癌基因。在FusOnC2财团感兴趣的癌症中，滑膜肉瘤的发病率最高 在美国和全世界，但一直是一种特别不受重视的恶性肿瘤，因为它倾向于 青少年和青壮年人口及其对系统治疗的相对较差的反应性， 与其他也与融合癌基因相关的儿童肉瘤相比。虽然生物学上的很多东西 SS18-SSX仍然未知，滑膜肉瘤患者代表着一种明显缺乏服务的孤儿疾病 在人群中，在癌症生物学光谱的极端有两个已经确立的原则。 首先，SS18-SSX已经证明了在小鼠身上重现滑膜肉瘤发生的能力 在不需要引入或随机获得二次遗传变化的情况下，第二个SS18-SSX 生化证明与一种重要的染色质重塑复合体SWI/SNF或 巴夫。这项申请建议建立三个研究项目，重点是转化的细胞生物学， 全基因组染色质生物学和SWI/SNF(BAF)复合组分生物学，每一个都与SS18- SSX。这些发现生物学和治疗靶标识别工作将由两个共享的 资源核心，将提供人类对治疗目标的验证和治疗的临床前测试 战略。调查组已经发展成为一个有机组合的合作网络， 在过去的十年中，每个项目都使用一个 多种功能筛选，一种新发现的起源细胞，能够在整个基因组范围内追踪SS18-SSX 定位和蛋白质相互作用--一个生产和评估重组SWI/SNF(BAF)的强大系统 具有可变成分的复合体，以及强大的滑膜肉瘤小鼠遗传模型-包括 转移性疾病的自发发展。初步数据足够稳健，足以建议 每个研究项目的治疗策略立即用于临床验证和评估 相关的小鼠模型和定量分子成像。

Overall: PROJECT SUMMARY/ABSTRACT (Parent Award) This application responds to RFA-CA-17-049 by proposing the establishment of a center distributed across three institutions with labs all focusing on the biology of the SS18-SSX (formerly called SYT-SSX) fusion oncogene. Among the FusOnC2 consortium cancers of interest, synovial sarcoma has the highest incidence in the United States and worldwide, but has been a specifically underserved malignancy due to its predilection for the adolescent and young adult population and its relatively poor responsiveness to systemic therapy, compared to other pediatric sarcomas that also associate with fusion oncogenes. While much of the biology of SS18-SSX remains unknown and synovial sarcoma patients represent a clearly underserved, orphan-disease population, there are two principles at the extremes of the cancer biology spectrum that are well established. First, SS18-SSX has proven the capacity to recapitulate synovial sarcomagenesis faithfully in the mouse without the need of introduced or stochastically acquired secondary genetic changes, second SS18-SSX has biochemically demonstrated interactions with an important chromatin remodeling complex called SWI/SNF or BAF. This application proposes to build three research projects focused on the cell biology of transformation, genome-wide chromatin biology and SWI/SNF (BAF) complex componentry biology, each related to SS18- SSX. These discovery biology and therapeutic target identification efforts will be supported by two shared resource cores that will provide human validation of therapeutic targets and preclinical testing of therapeutic strategies. The group of investigators has developed as an organically assembled network of collaborations, built over the last decade, during which time each project has gathered substantial preliminary data using a variety of functional screens, a newly identified cell of origin, the ability to track SS18-SSX genome wide localization and protein interactions, a powerful system to produce and evaluate recombinant SWI/SNF (BAF) complexes with variable componentry, and powerful mouse genetic models of synovial sarcoma—including spontaneous development of metastatic disease. Preliminary data are sufficiently robust to recommend therapeutic strategies immediately from each research project for the cores to validate and evaluate in clinically relevant mouse models and quantitative molecular imaging.