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:
- 金额:$ 57.86万
- 依托单位:
- 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:
- 关键词:ATAC-seqAccelerationAffectAreaBasic ScienceBiologyCell Cycle CheckpointCell LineCellsCellular StressChargeChildChildhood Soft Tissue SarcomaChildhood Solid NeoplasmClinicalClinical ResearchClinical TrialsClinical Trials Cooperative GroupClone CellsCollaborationsCommunicationComplexConsentDNA DamageDNA RepairDataDependenceDevelopmentDiseaseDoseDrug CombinationsDrug KineticsEnhancersEnsureEpigenetic ProcessEtiologyEvaluationExhibitsFRAP1 geneG2/M Checkpoint PathwayGene ExpressionGenetic TranscriptionGenomicsGoalsGovernmentHealthHomeostasisHumanImmunocompromised HostJournalsLong-Term SurvivorsMalignant Childhood NeoplasmMitoticModelingMusNatureOncogenicPIK3CG genePathway interactionsPatientsPersonsPharmaceutical PreparationsPharmacodynamicsPhasePhosphotransferasesPopulationPositioning AttributePreclinical TestingProteomicsPublishingQuality of lifeReceptor Protein-Tyrosine KinasesRecurrent diseaseReportingResearchResearch ProposalsRhabdomyosarcomaSaint Jude Children&aposs Research HospitalScheduleSignal PathwaySignal TransductionSoft tissue sarcomaSolid NeoplasmSomatic MutationStandardizationTestingTissuesTranslatingTranslational Researchanticancer researchburden of illnesscancer cellcellular targetingchemotherapyclinically relevantcurative treatmentsdrug use screeningexperiencegenomic datahigh-throughput drug screeningimplantationimprovedimproved outcomein vivoin vivo evaluationmolecular targeted therapiesneoplastic cellnext generationnovel drug combinationnovel therapeuticspatient derived xenograft modelpre-clinicalprogramsresponsesingle nucleus RNA-sequencingstandard of caretherapeutic targettranscriptomicstumortumor 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael A Dyer其他文献
Michael A Dyer的其他文献
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{{ truncateString('Michael A Dyer', 18)}}的其他基金
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
- 批准号:
10300360 - 财政年份:2021
- 资助金额:
$ 57.86万 - 项目类别:
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
- 批准号:
10437921 - 财政年份:2021
- 资助金额:
$ 57.86万 - 项目类别:
Cell-type– and developmental stage–specific regulation of gene expression in the retina
视网膜中基因表达的细胞类型和发育阶段的特异性调控
- 批准号:
10333227 - 财政年份:2020
- 资助金额:
$ 57.86万 - 项目类别:
Cell-type– and developmental stage–specific regulation of gene expression in the retina
视网膜中基因表达的细胞类型和发育阶段的特异性调控
- 批准号:
9886721 - 财政年份:2020
- 资助金额:
$ 57.86万 - 项目类别:
Novel Therapeutic Approaches for the Treatment of Neuroblastoma
治疗神经母细胞瘤的新方法
- 批准号:
10602395 - 财政年份:2020
- 资助金额:
$ 57.86万 - 项目类别:
Novel Therapeutic Approaches for the Treatment of Neuroblastoma
治疗神经母细胞瘤的新方法
- 批准号:
10372856 - 财政年份:2020
- 资助金额:
$ 57.86万 - 项目类别:
Novel Therapeutic Approaches for the Treatment of Neuroblastoma
治疗神经母细胞瘤的新方法
- 批准号:
10737754 - 财政年份:2020
- 资助金额:
$ 57.86万 - 项目类别:
Modeling Retinoblastoma Initiation Using 3D-Retinal Organoids
使用 3D 视网膜类器官模拟视网膜母细胞瘤的发生
- 批准号:
10611878 - 财政年份:2020
- 资助金额:
$ 57.86万 - 项目类别:
Cell-type– and developmental stage–specific regulation of gene expression in the retina
视网膜中基因表达的细胞类型和发育阶段的特异性调控
- 批准号:
10576348 - 财政年份:2020
- 资助金额:
$ 57.86万 - 项目类别:
Modeling Retinoblastoma Initiation Using 3D-Retinal Organoids
使用 3D 视网膜类器官模拟视网膜母细胞瘤的发生
- 批准号:
10165672 - 财政年份:2020
- 资助金额:
$ 57.86万 - 项目类别:
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