SPORE in Soft Tissue Sarcoma

软组织肉瘤中的孢子

基本信息

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
项目类别：
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

项目摘要

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.

抽象的 SPORE 在软组织肉瘤中的长期目标是降低软组织肉瘤的发病率和死亡率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，我们将集中精力努力实现 4 个广泛的转化研究目标： 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治疗靶点； 2. 定义机制对靶向治疗产生耐药性； 3. 临床验证软组织中的新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童群体提供服务； 4. 发现特定的分子改变和新的预测结果和对靶向治疗的反应的生物标志物。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综合性多学科小组，所有人员都配备了独特的资源，前瞻性收集超过 35 年的临床病理学和结果数据库时期。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。该数据库与广泛的肉瘤组织/血库链接，而该组织/血库又与广泛的多平台分子遗传学和表观遗传学数据集以及原发性肉瘤的集合人类肉瘤的细胞系和小鼠异种移植/PDX 模型。 SPORE 的结构围绕 4 研究项目、4 个核心以及职业提升和发展研究计划。每项研究项目重点关注上面列出的 4 个广泛的转化研究目标中的三个或更多。 RP-1（胃肠道间质瘤耐药性）旨在确定伊马替尼新的治疗靶点并制定新的治疗策略—— 耐药性胃肠道间质瘤，包括针对SDH缺乏性胃肠道间质瘤的大部分儿童亚群的策略。 RP-2（CDK4 靶向）旨在确定预测 CDK4 长期临床反应的治疗前生物标志物抑制剂治疗并寻找可以与 CDK4 抑制剂联合使用以发挥协同作用的药物增强衰老反应。 RP-3（致癌途径）旨在确定功效和 mTOR、PI3K、MEK 和致癌翻译 (eIF4A) 抑制剂单独和单独使用的分子效应联合治疗粘液纤维肉瘤和未分化多形性肉瘤，开发新的靶向药物治疗策略。 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揭示滑膜肉瘤的表观遗传和遗传脆弱性，目的是发现用于临床前和临床评价的药物靶点。