P3 - Target Discovery In Sarcoma Through Gemone-Wide Genetic and Functional Anal

我们的总体目标是对两种最常见的疾病进行综合性的分子遗传和功能分析 软组织肉瘤、粘液纤维肉瘤(MYXF)和多形性恶性纤维组织细胞瘤(PMFH)， 以阐明与肉瘤发生有关的突变程序和途径，并鉴定新的 治疗靶点。MYXF和PMFH的组织样本和细胞系将受到多平台的影响 蛋白质编码基因和microRNAs、DNA拷贝数的全基因组表达特征 改变、激活突变和基因重排。这些数据将被用来鉴定这两种基因 MYXF和PMFH的不同亚型和分子特征与肿瘤的形态，分级， 复发和存活率。为了确定潜在的治疗靶点，我们将筛选基因和microRNA 参与MYXF和PMFH细胞系的增殖、分化和存活。 潜在的靶点将通过在额外的细胞系和异种移植中的功能分析来验证。要实现 为了实现这些目标，我们组建了一个多学科的调查小组，配备了两个独特的资源： 前瞻性收集的8300多名接受治疗的患者的临床病理和结果数据的数据库 MSKCC的软组织肉瘤，以及一个拥有5500多个肉瘤样本和68个原发肿瘤样本的线性组织库 肉瘤细胞系。MSKCC与ROCL&FELLER之间的高度互动和协同合作将 确保最大限度地提高分子目标识别的生产率。生成的综合信息 将促进针对MYXF和PMFH的新的亚型特异性靶向治疗的开发。

Our overall goal is a compreiiensive molecular genetic and functional analysis of two of the most common soft tissue sarcomas, myxofibrosarcoma (MYXF) and pleomorphic malignant fibrous histiocytoma (PMFH), so as to elucidate the mutational programs and pathways involved in sarcomagenesis and to identify novel therapeutic targets. Tissue samples and cell lines of MYXF and PMFH will be subjected to a multiplatform genome-wide characterization of expression of protein-coding genes and microRNAs, DNA copy number changes, activating mutations, and gene rearrangements. These data will be used to identify both genetically distinct subtypes of MYXF and PMFH and molecular signatures associated with tumor morphology, grade, recurrence, and survival. To identify potential therapeutic targets, we will screen the genes and microRNAs in these signatures for involvement in proliferation, differentiation, and survival of MYXF and PMFH cell lines. Potential targets will be validated by functional assays in additional cell lines and in xenografts. To achieve these goals, we have assembled a multidisciplinary group of investigators armed with 2 unique resources: a database of prospectively collected clinical-pathologic and outcomes data on over 8300 patients treated for soft tissue sarcoma at MSKCC, and a linl<ed tissue banl< with over 5500 sarcoma samples and 68 primary sarcoma cell lines. The highly interactive and synergistic collaboration between MSKCC and Rocl<efeller will ensure maximum productivity in molecular target identification. The comprehensive information generated will facilitate the development of new subtype-specific targeted therapies for MYXF and PMFH.