SPORE in Soft Tissue Sarcoma

软组织肉瘤中的孢子

• 批准号: 10468957
• 负责人: SAMUEL SINGER
• 金额: $ 212.65万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468957
• 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; Prognosis; Research; Research Personnel; Research Project Grants; Resistance; Resources; Scientist; Signal Pathway; Soft tissue sarcoma; Standardization; Structure; Systemic Therapy; Therapeutic; Tissues; Translational Research; Translations; Xenograft Model; Xenograft procedure; advanced disease; animal model development; base; biomarker validation; cBioPortal; career; clinical application; clinical care; design; experience; functional genomics; human model; improved; inhibitor therapy; insight; inter-institutional; mTOR Inhibitor; mortality; multidisciplinary; new therapeutic target; novel; outcome prediction; patient derived xenograft model; patient population; preclinical evaluation; predicting response; predictive marker; prognostication; 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.

抽象的 软组织肉瘤中孢子的长期目标是降低来自 软组织肉瘤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的肉瘤类型和亚型。为了追求这一点，我们将集中精力 在4个广泛的转化研究目标上的努力：1。定义共享和类型特定的分子 肉体作用的机制，以识别新的理性治疗靶标； 2。定义机制 对靶向疗法的抵抗力； 3。临床验证软软的新治疗靶标和治疗 组织肉瘤患者并促进临床试验的开发，招募和应用 服务成人和小儿种群； 4。发现特定的分子改变和新的变化 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 编制了一个综合的，多学科的基本和临床研究人员，所有这些都武装着 独特的资源，一种临床病理学和结果数据库，可预期收集35年 时期。现在，该数据库包含了超过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/血库有关，这又与 广泛的多平台分子遗传和表观遗传数据集以及一系列原代肉瘤 人肉瘤的细胞系和小鼠异种移植/PDX模型。孢子结构左右4 研究项目，4个核心以及职业增强和发展研究计划。每个研究 项目重点介绍了上面列出的四个广泛的翻译研究目标中的三个或多个。 RP-1（要点 抵抗）旨在确定新的治疗靶标，并为伊马替尼制定新的治疗策略 抵抗力的要点，包括带有SDH缺陷要素的大部分儿科子集的策略。 RP-2（CDK4 靶向）旨在确定治疗前的生物标志物预测对CDK4的临床反应的预测 抑制剂疗法并找到可以与CDK4抑制作用的药物 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）的分子效应，单独和中 组合，在粘液纤维肉瘤和未分化的多形性肉瘤中，开发了新的靶向目标 治疗策略。 RP-4（功能基因组筛选）将执行基于CRISPR的功能基因组 在滑膜肉瘤中发现表观遗传和遗传脆弱性的筛选，目的是发现 临床前和临床评估的药物靶标。