In Vivo Testing of Novel Drug Combinations for Pediatric Soft Tissue Sarcomas

治疗小儿软组织肉瘤的新型药物组合的体内测试

基本信息

批准号：
10437921
负责人：
Michael A Dyer
金额：
$ 75.2万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10437921
关键词：
ATAC-seq Affect Area Basic Science Biology Cell Cycle Checkpoint Cell Line Cell Nucleus Cells Cellular Stress Charge Child Childhood Soft Tissue Sarcoma Childhood Solid Neoplasm Clinical Clinical Research Clinical Trials Clinical Trials Cooperative Group Clone Cells Communication Complex Consent DNA Damage DNA Repair Data Data Analyses Dependence Development Disease Dose Drug Combinations Drug Kinetics Enhancers Ensure Epigenetic Process Etiology Evaluation Exhibits FRAP1 gene G2/M Checkpoint Pathway Gene Expression Genetic Transcription Genomics Goals Government Health Homeostasis Human Immunocompromised Host Journals Long-Term Survivors Malignant Childhood Neoplasm Mitotic Modeling Mus Nature Oncogenic Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacodynamics Phase Phosphotransferases Population Positioning Attribute Preclinical Testing Proteomics Publishing Quality of life Receptor Protein-Tyrosine Kinases Recurrence Recurrent disease Reporting Research Research Proposals Rhabdomyosarcoma Saint Jude Children&apos s Research Hospital Schedule Signal Pathway Signal Transduction Small Nuclear RNA Soft tissue sarcoma Solid Neoplasm Somatic Mutation Standardization Testing Tissues Translating Translational Research anticancer research base burden of illness cancer cell cellular targeting chemotherapy clinically relevant curative treatments drug use screening experience genomic data high-throughput drug screening implantation improved improved outcome in vivo in vivo evaluation molecular targeted therapies neoplastic cell next generation novel drug combination novel therapeutics patient derived xenograft model pre-clinical programs response standard of care therapeutic target transcriptome sequencing transcriptomics tumor tumor heterogeneity

项目摘要

PROJECT SUMMARY Despite the advances made in our understanding of the etiology of pediatric soft tissue sarcomas (STS), the overall survival of those diseases has not significantly improved in over 2 decades. For children with recurrent disease, survival is below 30%, and long-term survivors have an increased burden of disease associated with the curative therapies they received. Therefore, the goal of our research team is to improve the survival and quality of life of children with STS by integrating basic, translational, and clinical research. For the past 10 years, we have consented STS and other solid tumor patients to donate tissue for orthotopic implantation into immunocompromised mice to develop orthotopic patient derived xenografts (O-PDXs). Our O-PDXs have been used for ex vivo high- throughput drug screening and in vivo testing using a standardized preclinical phase I, II, III paradigm. Rhabdomyosarcoma (RMS) is the most common STS in children and genomic studies have shown that rare subsets of clonally related cells can survive treatment and contribute to disease recurrence. Subsequent integrated analyses using transcriptomic, epigenetic and proteomic data showed that RMS tumors retain lineage-specific transcriptional and epigenetic signatures of their developmental origins. More recently, single cell and single nucleus RNA-seq (sc/snRNA-seq) and in vivo lineage-tracing showed that clones of cells can transition through their normal developmental programs. Indeed, single- cell ATAC-seq demonstrated that the cell- and developmental stage–specific super-enhancer activity is correlated with those clonal changes in gene expression. Chemotherapy eliminates the most proliferative tumor cell populations, and the surviving dormant tumor cells rapidly expand and re- establish their developmental hierarchy, which leads to disease recurrence. This is a striking example of the complex cell-intrinsic and -extrinsic signaling within STS and the intricate connection between developmental and oncogenic pathways in childhood cancer. In this proposal, we will perform in vivo testing for 8-10 drugs per year using our STS O-PDX models. The most compelling pathways are developmental kinase pathways (Aim 1), cell stress pathways (Aim 2) and G2/M cell cycle checkpoints (Aim 3). Novel drug combinations will be tested as well as those that include conventional chemotherapy for standard of care. Particular emphasis will be placed on eliminating all the clones in the tumor to improve survival by reducing disease recurrence.

项目概要尽管我们对小儿软组织肉瘤病因的了解取得了进展（STS），这些疾病的总体生存率在二十多年来没有显着改善。患有复发性疾病的儿童，生存率低于30%，而长期生存者的生存率则有所增加因此，我们的目标是与他们接受的治疗相关的疾病负担。研究团队的目标是通过整合基础、在过去的 10 年里，我们已经同意 STS 和其他实体研究。肿瘤患者捐献组织用于原位植入免疫功能低下的小鼠体内以进行开发原位患者衍生异种移植物 (O-PDX) 我们的 O-PDX 已用于离体高移植物。使用标准化临床前 I、II、III 期范式进行吞吐量药物筛选和体内测试。横纹肌肉瘤 (RMS) 是儿童中最常见的 STS，基因组研究表明克隆相关细胞的罕见亚群可以在治疗后存活并导致疾病复发。随后使用转录组、表观遗传学和蛋白质组数据进行的综合分析表明 RMS 肿瘤保留了其发育起源的谱系特异性转录和表观遗传特征。最近，单细胞和单核 RNA-seq (sc/snRNA-seq) 和体内谱系追踪表明细胞克隆可以通过其正常的发育程序进行转变。 cell ATAC-seq 证明细胞和发育阶段特异性超级增强子活性与基因表达的那些克隆变化相关的化学疗法消除了大部分。增殖的肿瘤细胞群，以及存活的休眠肿瘤细胞迅速扩张并重新建立他们的发育等级，从而导致疾病复发，这是一个引人注目的例子。 STS 内复杂的细胞内在和外在信号传导以及它们之间错综复杂的联系在这项提案中，我们将在体内进行儿童癌症的发育和致癌途径。每年使用我们的 STS O-PDX 模型测试 8-10 种药物最引人注目的途径是。发育激酶途径（目标 1）、细胞应激途径（目标 2）和 G2/M 细胞周期检查点（目标 3）将测试新药物组合以及包含常规药物的组合。标准护理的化疗将特别强调消除所有克隆。肿瘤通过减少疾病复发来提高生存率。