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.

项目摘要尽管我们对小儿软组织病因的理解取得了进步（STS），这些疾病的总体生存率在20多年中没有显着改善。为了复发性疾病的儿童，生存率低于30％，长期存活率增加与他们接受的治疗疗法有关的疾病负担。因此，我们的目标研究团队将通过整合基本，翻译和临床研究。在过去的10年中，我们已同意STS和其他牢固肿瘤患者将组织捐赠到原位植入到免疫功能低下的小鼠中以发展原位患者衍生的Xenographictic（O-PDXS）。我们的O-PDX已用于离体高 - 使用标准临床前II，II，III范式使用标准化的临床前术筛选吞吐药物筛查和体内测试。横纹肌肉瘤（RMS）是儿童中最常见的ST，基因组研究表明，克隆相关细胞的罕见子集可以在治疗中生存并导致疾病复发。随后使用转录组，表观遗传学和蛋白质组学数据进行的综合分析表明RMS 肿瘤保留其发育起源的谱系特异性转录和表观遗传学特征。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发育程序过渡。确实，单一细胞atac-seq表明细胞和发育阶段 - 特异性超增强剂的活性是与基因表达的克隆变化相关。化学疗法最多增殖的肿瘤细胞群体，并且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，导致疾病复发。这是一个罢工例子 STS内的复杂细胞中心和 - 超级信号传导以及错综复杂的连接儿童癌症中的发育和致癌途径。在此提案中，我们将在体内执行使用我们的STS O-PDX型号每年测试8-10种药物。最引人注目的途径是发育激酶途径（AIM 1），细胞应力途径（AIM 2）和G2/M细胞周期检查点（目标3）。新型药物组合以及包括常规的药物组合护理标准的化学疗法。特别强调将消除所有克隆通过减少疾病复发来改善生存的肿瘤。