SPORE in Soft Tissue Sarcoma

软组织肉瘤中孢子的长期目标是通过开发针对肉瘤类型和亚型特有的分子、遗传、表观遗传和信号通路改变的治疗方法来降低软组织肉瘤的发病率和死亡率。为了实现这一目标，我们将致力于三个广泛的转译研究目标：1.确定共同的和特定类型的肉瘤发生的分子机制，以确定新的合理的治疗靶点；2.确定靶向治疗的耐药机制；3.在临床研究中开发和验证靶向治疗。为了实现这些目标，我们组织了一个综合的、多学科的基础和临床研究小组，他们都拥有独特的资源，一个前瞻性地收集了27年来临床病理和结果数据库，其中包含MSKCC治疗软组织肉瘤的8300多名患者的数据。该数据库在过去16年中一直与一个机构组织库相关联，在过去7年中一直与建立原代肉瘤细胞系和人类肉瘤小鼠异种移植模型的全面组织采购过程相关联。孢子由4个研究项目、3个核心以及职业发展和发展研究计划构成。每个研究项目都集中于上面列出的三个广泛的翻译研究目标中的至少一个。RP-1(伊马替尼耐药)旨在为儿童和伊马替尼耐药的GIST寻找新的治疗靶点和开发新的治疗策略。RP-2(PDGFR/PI3K/mT0R靶向)利用细胞系、异种移植模型和II期临床试验评估了针对PDGFRA信号转导和减少滑膜肉瘤和肉瘤类型中激活的Akt的策略，这些肿瘤显示PDGFRA表达增加。RP-3(靶点发现)旨在确定粘液纤维肉瘤和多形性恶性纤维组织细胞瘤的致癌基因组驱动因素，从而确定新的治疗靶点。RP-4(表观遗传疗法)旨在阐明滑膜肉瘤SYT-SSX靶基因失控所涉及的表观遗传学机制和组蛋白密码的改变，以加深我们对滑膜肉瘤发病机制的认识，并指导新的选择性表观遗传疗法的发展。

The long-term goal of the SPORE in Soft Tissue Sarcoma is to reduce morbidity and mortality from soft tissue sarcoma by developing therapies targeted to the molecular, genetic, epigenetic, and signaling pathway alterations that are specific to sarcoma type and subtype. To pursue this, we will focus our efforts on 3 broad translational research objectives: 1. Define shared and type-specific molecular mechanisms of sarcomagenesis to identify new rational therapeutic targets, 2. Define mechanisms of resistance to targeted therapies, 3. Develop and validate targeted therapies in clinical studies. To achieve these goals we have marshaled an integrated, multidisciplinary group of basic and clinical investigators all armed with a unique resource, a clinicopathologic and outcomes database prospectively collected over a 27-year period containing data for over 8300 patients treated for soft tissue sarcoma at MSKCC. This database has been linked for the past 16 years to an institutional tissue bank, and for the past 7 years to a comprehensive tissue procurement process for establishment of primary sarcoma cell lines and mouse xenograft models of human sarcoma. The SPORE is structured around 4 research projects, 3 cores, and career development and developmental research programs. Each research project focuses on at least one of the 3 broad translational research goals listed above. RP-1 (Imatinib Resistance) aims to identify new therapeutic targets and develop new treatment strategies for pediatric and imatinib-resistant GIST. RP-2 (PDGFR/PI3K/mT0R Targeting) evaluates strategies for targeting PDGFRA signaling and reducing activated Akt in synovial sarcoma and sarcoma types that show increased expression of PDGFRA using cell lines, xenograft models, and phase II clinical trials. RP-3 (Target Discovery) aims to identify genomic drivers of oncogenesis in myxofibrosarcoma and pleomorphic malignant fibrous histiocytoma so as to identify new therapeutic targets. RP-4 (Epigenetic Therapy) aims to elucidate the epigenetic mechanisms and histone code alterations involved in the deregulation of SYT-SSX target genes in synovial sarcoma so as to enhance our understanding of synovial sarcoma pathogenesis and guide the development of new selective epigenetic therapies.