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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：
10653061
负责人：
Michael A Dyer
金额：
$ 57.86万
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/10653061
关键词：
ATAC-seq Acceleration Affect Area Basic Science Biology Cell Cycle Checkpoint Cell Line Cells Cellular Stress Charge Child Childhood Soft Tissue Sarcoma Childhood Solid Neoplasm Clinical Clinical Research Clinical Trials Clinical Trials Cooperative Group Clone Cells Collaborations Communication Complex Consent DNA Damage DNA Repair Data 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 PIK3CG gene Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacodynamics Phase Phosphotransferases Population Positioning Attribute Preclinical Testing Proteomics Publishing Quality of life Receptor Protein-Tyrosine Kinases Recurrent disease Reporting Research Research Proposals Rhabdomyosarcoma Saint Jude Children&apos s Research Hospital Schedule Signal Pathway Signal Transduction Soft tissue sarcoma Solid Neoplasm Somatic Mutation Standardization Testing Tissues Translating Translational Research anticancer research 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 single nucleus RNA-sequencing standard of care therapeutic target 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.

项目总结