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.

摘要