Singer SPORE Supplement

歌手 SPORE 补充品

• 批准号: 10912166
• 负责人: SAMUEL SINGER
• 金额: $ 91.86万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10912166
• 关键词: Address; Adult; Advisory Committees; Affinity; Animal Model; Animals; Autophagocytosis; Award; Bioinformatics; Biological Specimen Banks; Biology; Biometry; Blood Banks; CDK4 gene; CRISPR/Cas technology; Cell Line; Cell Survival; Cells; Childhood; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Clinical Trials Unit; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Collection; Combined Modality Therapy; Communication; Communities; Complement; Complex; Cyclin-Dependent Kinase Inhibitor 2A; Data; Data Set; Databases; Development; Diagnosis; Disease; Drug Targeting; ETV1 gene; EZH2 gene; Education; Engineering; Ensure; Epigenetic Process; Ethnic Population; Evaluation; FRAP1 gene; Fibroblast Growth Factor Receptors; Gastrointestinal Stromal Tumors; Generations; Genes; Genetic; Genetic Predisposition to Disease; Goals; Growth; Human; Image; Imatinib; Immune; Immunocompetent; In Vitro; Individual; Institution; Integrins; Laboratories; Laboratory Research; Link; MDM2 gene; MEKs; Malignant Fibrous Histiocytoma; Messenger RNA; Methodology; Modeling; Molecular; Molecular Analysis; Molecular Genetics; Molecular Profiling; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mus; Myxoid Malignant Fibrous Histiocytoma; Oncogenic; Open Reading Frames; Operative Surgical Procedures; Outcome; PIK3CG gene; Participant; Pathologic; Pathway interactions; Patient advocacy; Patients; Performance; Personnel Management; Pharmaceutical Preparations; Phosphoproteins; Phosphotransferases; Population; Prognosis; Protein Isoforms; Proteins; Proteomics; Publishing; RNA Helicase; Research; Research Personnel; Research Project Grants; Research Support; Resistance; Resources; Role; Sampling; Signal Pathway; Signal Transduction; Soft tissue sarcoma; Structure; Systemic Therapy; TP53 gene; Testing; Tissue Banks; Tissue Sample; Tissues; Translating; Translational Research; Translations; Update; Validation; Xenograft procedure; advanced disease; biomarker identification; blood resource; career; clinical application; design; efficacy evaluation; functional genomics; human model; human tissue; in vitro activity; in vivo; in vivo Model; inhibitor; inhibitor therapy; insight; mTOR Inhibitor; mTOR inhibition; member; molecular pathology; mortality; mouse model; multidisciplinary; mutation screening; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; outcome prediction; patient derived xenograft model; pre-clinical; preclinical evaluation; predicting response; predictive marker; programs; prospective; quality assurance; racial population; recruit; research clinical testing; resistance mechanism; resistance mutation; response; sarcoma; senescence; synovial sarcoma; targeted sequencing; targeted treatment; therapeutic development; therapeutic target; therapy development; therapy resistant; tissue preparation; tissue resource; translational cancer research; treatment response; treatment strategy; tumor; tumor DNA

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.

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名在MS接受软组织肉瘤治疗的患者的数据。 该数据库连接到一个广泛的肉瘤组织/血液库，这反过来又连接到一个广泛的 多平台分子遗传学和表观遗传学数据集以及原代肉瘤细胞系的集合， 人肉瘤的小鼠异种移植物/PDX模型。SPORE围绕4个研究项目展开， 4个核心，以及职业提升和发展研究计划。每个研究项目都聚焦于 在上面列出的四个广泛的转化研究目标中的三个或更多。RP-1（GIST抗性）目标 为了确定新的治疗靶点并开发新的伊马替尼耐药GIST的治疗策略， 包括针对主要为患有SDH缺陷型GIST的儿科亚组的策略。RP-2（CDK 4靶向） 寻求鉴定预测对CDK 4抑制剂的长期临床应答的治疗前生物标志物 治疗，并找到可以与CDK 4抑制剂联合使用的药物， 衰老反应RP-3（致癌途径）旨在确定疗效和分子效应 mTOR、PI 3 K、MEK和致癌翻译（eIF 4A）的抑制剂单独和组合， 粘液纤维肉瘤和未分化多形性肉瘤开发新的靶向治疗 战略布局RP-4（功能基因组筛选）将进行基于CRISPR的功能基因组筛选 揭示滑膜肉瘤的表观遗传和遗传脆弱性， 临床前和临床评价的目标。

项目成果

The epigenomics of sarcoma.

• DOI: 10.1038/s41568-020-0288-4
• 发表时间: 2020-10
• 期刊: Nature reviews. Cancer
• 作者: Nacev BA;Jones KB;Intlekofer AM;Yu JSE;Allis CD;Tap WD;Ladanyi M;Nielsen TO
• 通讯作者: Nielsen TO

The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing.

• DOI: 10.1038/s43018-020-0080-0
• 发表时间: 2020
• 期刊: Nature cancer
• 影响因子: 22.7
• 作者: Parsa S;Ortega-Molina A;Ying HY;Jiang M;Teater M;Wang J;Zhao C;Reznik E;Pasion JP;Kuo D;Mohan P;Wang S;Camarillo JM;Thomas PM;Jain N;Garcia-Bermudez J;Cho BK;Tam W;Kelleher NL;Socci N;Dogan A;De Stanchina E;Ciriello G;Green MR;Li S;Birsoy K;Melnick AM;Wendel HG
• 通讯作者: Wendel HG

Rocaglates as Antivirals: Comparing the Effects on Viral Resistance, Anti-Coronaviral Activity, RNA-Clamping on eIF4A and Immune Cell Toxicity.

作为抗病毒药：比较对病毒耐药性，抗核心病毒活性的影响，对EIF4A的RNA钳位和免疫细胞毒性的影响。

• DOI: 10.3390/v14030519
• 发表时间: 2022-03-03
• 期刊: Viruses
• 作者: Obermann W;Friedrich A;Madhugiri R;Klemm P;Mengel JP;Hain T;Pleschka S;Wendel HG;Hartmann RK;Schiffmann S;Ziebuhr J;Müller C;Grünweller A
• 通讯作者: Grünweller A

ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements.

• DOI: 10.1002/gcc.22454
• 发表时间: 2017-06
• 期刊: Genes, chromosomes & cancer
• 作者: Kao YC;Sung YS;Chen CL;Zhang L;Dickson BC;Swanson D;Vaiyapuri S;Latif F;Alholle A;Huang SC;Hornick JL;Antonescu CR
• 通讯作者: Antonescu CR

Primary renal sarcoma with SS18::POU5F1 gene fusion.

• DOI: 10.1002/gcc.23053
• 发表时间: 2022-09
• 期刊: GENES CHROMOSOMES & CANCER
• 影响因子: 3.7
• 作者: Argani, Pedram;Matoso, Andres;Gross, John M.;Zhang, Yanming;SoRelle, Jeffrey A.;Gagan, Jeffrey;Antonescu, Cristina R.;Palsgrove, Doreen
• 通讯作者: Palsgrove, Doreen