SPORE in Soft Tissue Sarcoma

软组织肉瘤中的孢子

• 批准号: 10016084
• 负责人: SAMUEL SINGER
• 金额: $ 217.02万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016084
• 关键词: Adult; Animal Cancer Model; Biological; Biology; Blood Banks; CDK4 gene; Cancer Center Support Grant; Cell Line; Childhood; Clinic; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Collection; Combined Modality Therapy; Complex; Core Facility; Cyclin-Dependent Kinase Inhibitor 2A; Data; Data Set; Databases; Development; Diagnosis; Disease; Drug Targeting; Epigenetic Process; Genetic; Genetic Predisposition to Disease; Goals; Grant; Growth; Histologic; Human; Imatinib; Infrastructure; Institution; Investigation; Investigational Therapies; Link; MEKs; Malignant Fibrous Histiocytoma; Malignant Neoplasms; Marshal; Medical Informatics; Memorial Sloan-Kettering Cancer Center; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Mus; Myxoid Malignant Fibrous Histiocytoma; Natural History; Nomograms; Oncogenic; Operative Surgical Procedures; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Population; Research; Research Personnel; Research Project Grants; Resistance; Resources; Scientist; Signal Pathway; Soft tissue sarcoma; Standardization; Structure; Systemic Therapy; Therapeutic; Tissues; Translational Research; Translations; Xenograft procedure; advanced disease; animal model development; base; biomarker validation; cBioPortal; career; clinical application; clinical care; design; experience; functional genomics; human model; improved; insight; inter-institutional; mTOR Inhibitor; mortality; multidisciplinary; new therapeutic target; novel; outcome forecast; outcome prediction; patient population; preclinical evaluation; predicting response; predictive marker; prognostic; programs; prospective; ranpirnase; recruit; research clinical testing; resistance mechanism; response; sarcoma; senescence; specific biomarkers; synovial sarcoma; targeted treatment; therapeutic target; therapy development; treatment strategy; tumor

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 MSKCC. 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.

摘要 SPORE在软组织肉瘤中的长期目标是降低 通过开发针对特定分子、遗传、表观遗传和 信号通路改变或特定肉瘤类型和亚型。为了实现这一目标，我们将集中精力 致力于4个广泛的翻译研究目标：1。定义共享和类型特异性分子 肉瘤发生机制，以确定新的合理的治疗靶点; 2.定义以下机制 对靶向治疗的抗性; 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 生物标志物预测结果和对靶向治疗的反应。为了实现这些目标，我们 组织了一个由基础和临床研究人员组成的综合性多学科小组，所有人都配备了 独特的资源，前瞻性收集了35年的临床病理和结果数据库 期该数据库现在包含超过11，840名接受软组织肉瘤治疗的患者的数据， MSKCC。该数据库连接到一个广泛的肉瘤组织/血库，而后者又连接到一个 广泛的多平台分子遗传和表观遗传数据集以及原发性肉瘤的集合 细胞系和人肉瘤的小鼠异种移植物/PDX模型。孢子的结构围绕4 研究项目，4个核心，职业提升和发展研究计划。每个研究 该项目侧重于上述4个广泛的转化研究目标中的三个或更多。RP-1（GIST Resistance）旨在为伊马替尼确定新的治疗靶点并开发新的治疗策略- 耐药GIST，包括策略，主要是儿科子集与SDH缺陷GIST。RP-2（CDK4 靶向）寻求鉴定预测对CDK 4的延长临床应答的治疗前生物标志物 抑制剂治疗，并找到可以与CDK 4抑制剂联合使用的药物， 增强衰老反应。RP-3（致癌途径）旨在确定疗效和 mTOR、PI 3 K、MEK和致癌翻译（eIF 4A）抑制剂单独和联合应用的分子效应 组合，在粘液纤维肉瘤和未分化多形性肉瘤，以开发新的靶向 治疗策略。RP-4（功能基因组筛选）将进行基于CRISPR的功能基因组筛选， 筛选以揭示滑膜肉瘤的表观遗传和遗传弱点，目的是发现 用于临床前和临床评价的药物靶点。