Singer SPORE Supplement

摘要 软组织肉瘤中孢子的长期目标是减少因 软组织肉瘤通过开发针对特定分子、基因、表观遗传学和 信号通路改变或特定肉瘤类型和亚型。为了追求这一点，我们将集中我们的 致力于四个广泛的翻译研究目标：1.定义共享和特定类型的分子 肉瘤发生机制以寻找新的合理治疗靶点；2.明确肿瘤的发生机制 对靶向治疗的抵抗；3.临床验证新的治疗靶点和治疗方法 组织肉瘤患者，并促进临床试验的开发、招募和应用 为成人和儿科人群提供服务；4.发现特定的分子变化和新的 预测靶向治疗结果和反应的生物标记物。为了实现这些目标，我们有 组建了一个由基础和临床研究人员组成的多学科综合小组，所有人都配备了 独特的资源，一个预期在35年内收集的临床病理和结果数据库 句号。这个数据库现在包含了在MS接受软组织肉瘤治疗的11,840多名患者的数据。 该数据库链接到一个广泛的肉瘤组织/血库，而后者又链接到一个广泛的 多平台分子遗传学和表观遗传学数据集和一组原代肉瘤细胞系和 小鼠异种移植/PDX人肉瘤模型。孢子由4个研究项目组成， 4个核心，以及职业提升和发展研究计划。每个研究项目都集中在 以上列出的四大翻译研究目标中的三个或更多。RP-1(GIST阻力)目标 为了确定对伊马替尼耐药的GIST的新治疗靶点和开发新的治疗策略， 包括针对SDH缺陷的GIST以儿科为主的子集的策略。RP-2(CDK4靶向) 寻求找出一种治疗前预测CDK4抑制剂延长临床反应的生物标志物 并寻找可以与CDK4抑制联合使用的药物，以协同增强 衰老反应。RP-3(致癌途径)寻求确定疗效和分子效应 MTOR、PI3K、MEK和致癌翻译(EIF4A)的抑制剂，单独和联合使用，在 粘液纤维肉瘤和未分化多形性肉瘤开发新的靶向治疗 战略。RP-4(功能基因组筛选)将执行基于CRISPR的功能基因组筛选 揭示滑膜肉瘤的表观遗传和遗传易感性，以期发现药物 临床前和临床评估的目标。

ABSTRACT The long-term goal of the SPORE in Soft Tissue Sarcoma is to reduce the morbidity and mortality from soft tissue sarcoma by developing therapies targeted to specific molecular, genetic, epigenetic, and signaling pathway alterations or specific sarcoma type and subtype. To pursue this, we will focus our efforts on 4 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. Clinically validate new therapeutic targets and treatments in soft tissue sarcoma patients and facilitate the development, recruitment, and application of clinical trials that serve both the adult and pediatric populations; 4. Discover specific molecular alterations and new biomarkers that predict outcome and response to targeted therapy. 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 35-year period. This database now contains data for over 11,840 patients treated for soft tissue sarcoma at MS. The database is linked to an extensive sarcoma tissue/blood bank, which in turn is linked to an extensive multi-platform molecular genetic and epigenetic dataset and a collection of primary sarcoma cell lines and mouse xenograft/PDX models of human sarcoma. The SPORE is structured around 4 research projects, 4 cores, and career enhancement and developmental research programs. Each research project focuses on three or more of the 4 broad translational research goals listed above. RP-1 (GIST Resistance) aims to identify new therapeutic targets and develop new treatment strategies for imatinib- resistant GIST, including strategies for the largely pediatric subset with SDH-deficient GIST. RP-2 (CDK4 Targeting) seeks to identify a pre-treatment biomarker predictive of prolonged clinical response to CDK4 inhibitor therapy and to find drugs that can be combined with CDK4 inhibition to synergistically augment the senescence response. RP-3 (Oncogenic Pathways) seeks to determine the efficacy and molecular effects of inhibitors of mTOR, PI3K, MEK, and oncogenic translation (eIF4A), alone and in combination, in myxofibrosarcoma and undifferentiated pleomorphic sarcoma to develop new targeted treatment strategies. RP-4 (Functional Genomic Screens) will perform CRISPR-based functional genomic screens to uncover epigenetic and genetic vulnerabilities in synovial sarcoma with the aim of discovering drug targets for preclinical and clinical evaluation.