Soft Tissue Sarcoma Program Project

描述(由申请人提供)：本竞争性提交建议书(CA47179-15)中描述的计划的总体目标是继续采用多学科综合方法研究软组织肉瘤的生物学、发病机制、进展和自然病史，然后利用这些知识确定可在I期和II期临床试验中进行临床测试的新治疗靶点。其具体目标是：1)提高诊断和预测；2)通过基因发现和通路分析寻找肉瘤新的分子和生化靶点；3)开发新的靶向分子疗法；4)在临床研究中验证分子和生化靶点。为了实现这些目标，我们召集了一个综合的、多学科的研究小组，所有人都拥有一个独特的资源，一个前瞻性地在23年间收集的临床病理和结果数据库，其中包含在MSKCC接受软组织肉瘤治疗的6486名患者。在过去12年中，该数据库一直与一个机构组织库相关联，并且在过去3年中，与建立原代肉瘤细胞系和人类肉瘤小鼠异种移植模型的综合组织采购过程相关联。这一续签申请包含重大变化，增加了两个全新的项目，这两个项目与正在进行的两个项目密切互动，并建立了一个新的生物信息学核心。在脂肪肉瘤生物学的新创举项目1中，我们将使用集成的基因表达和核磁共振生化分析来改进诊断和预测，并确定新的治疗靶点和脂肪肉瘤发生的关键细胞途径。在项目2中，我们将研究PTEN/AKT信号网络如何调节Rb和P53通路中的基因，以控制细胞周期和细胞凋亡。项目3是一个开发靶向治疗的全新项目，它将确定调节细胞周期的新疗法，并将这些临床前发现转化为肉瘤患者的临床癌症治疗。在项目4中，我们将继续定义滑膜肉瘤的分子遗传学，特别强调通过对差异表达的酪氨酸激酶基因的突变分析来识别新的分子靶点。这4个项目得到了三个核心的支持：行政学、病理学和生物信息学。所有项目和核心之间的高度集成协作将确保最大限度地提高生产率，并将通过基因发现和路径分析加强分子和生化目标识别。这些信息将被用于开发针对软组织肉瘤的新的靶向分子疗法。

DESCRIPTION (provided by applicant): The overall goal of the program described in this competing submission proposal (CA47179-15) is to continue an integrated multidisciplinary approach to the investigation of the biology, pathogenesis, progression and natural history of soft tissue sarcoma and then use this knowledge to identify novel therapeutic targets that can be tested clinically in phase I and II clinical trials. The specific goals are to: 1) improve diagnosis and prognostication 2) identify new molecular and biochemical targets in sarcoma through gene discovery and pathway analysis 3) develop new targeted molecular therapeutics and 4) validate molecular and biochemical targets in clinical studies. To achieve these goals we have marshaled an integrated, multidisciplinary group of investigators all armed with a unique resource, a clinicopathological and outcomes database prospectively collected over a 23 year period containing over 6486 patients treated for soft tissue sarcoma at MSKCC. This database has been linked to an institutional tissue bank for the past 12 years and, for the past 3 years, to a comprehensive tissue procurement process for establishment of primary sarcoma cell lines and mouse xenograft models of human sarcoma. This renewal application contains substantial changes with the addition of two entirely new projects, which interact closely with the two continuing projects and the establishment of a new bioinformatics core. In Project 1, a new initiative in liposarcoma biology, we will use an integrated gene expression and NMR biochemical analysis to improve diagnosis and prognostication and to identify new therapeutic targets and cellular pathways critical to liposarcoma tumorigenesis. In Project 2, we will study how the PTEN/AKT signaling network regulates genes in the RB and p53 pathway to control cell cycle and apoptosis. Project 3, an entirely new project on development of targeted therapeutics, will identify new therapies that modulate the cell cycle and translate these preclinical discoveries into clinical cancer therapy for sarcoma patients. In Project 4, we will continue to define the molecular genetics of synovial sarcoma with a particular emphasis on identification of new molecular targets through mutational analysis of differentially expressed tyrosine kinase genes. These 4 projects are supported by 3 cores: Administrative, Pathology, and Bioinformatics. The highly integrated collaboration between all projects and cores will ensure maximum productivity and will enhance molecular and biochemical target identification through gene discovery and pathway analysis. This information will then be used to develop new targeted molecular therapeutics for soft tissue sarcoma.