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Mediators Of Arrested Differentiation In Pediatric Rhabdomyosarcoma

小儿横纹肌肉瘤分化停滞的介质

基本信息

批准号：
10559589
负责人：
Mark Edward Hatley
金额：
$ 40.24万
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：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10559589
关键词：
AKT1 gene Acute Promyelocytic Leukemia Affinity Chromatography Attenuated Automobile Driving Binding Binding Sites Biological Assay Biology Cell Nucleus Cells Child Childhood Childhood Brain Neoplasm Childhood Rhabdomyosarcoma Clinical Trials Coupled DNA sequencing Development Differentiation Therapy Dissection Embryonal Rhabdomyosarcoma Ependymoma FOXO1A gene FRAP1 gene Gene Expression Profile Gene Fusion Genes Genetic Engineering Genetic Transcription Genetically Engineered Mouse Goals Human Hypermethylation In Vitro Isotretinoin Knowledge Laboratories Luciferases MM form creatine kinase Malignant Neoplasms Malignant neoplasm of brain Mass Spectrum Analysis Mediator Modeling Molecular Mus Muscle Development Mutation Myoblasts Neuroblastoma Neurons Nucleic Acid Regulatory Sequences PAX3 gene PAX7 gene PIK3CG gene PTEN gene Pathway interactions Penetrance Pharmacotherapy Phenotype Proteins Proto-Oncogene Proteins c-akt Quantitative Reverse Transcriptase PCR Regulation Reporter Rhabdomyosarcoma Role Signal Transduction Skeletal Muscle Soft tissue sarcoma Testing Therapeutic Transcription Repressor Transgenic Mice Tretinoin Work aggressive therapy chromatin immunoprecipitation design experimental study gain of function high risk in vitro Assay in vivo insight loss of function medulloblastoma mouse model mutant novel novel therapeutics overexpression progenitor promoter tumor

项目摘要

Project Summary/Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Despite rigorous clinical trials the survival for children with high-risk RMS has not changed for three decades. The children that do survive often suffer from life-long disfigurements as a result of the aggressive treatment. RMS is subdivided into two major classes, fusion-positive (FP-RMS) and fusion-negative (FN-RMS), based on the presence or absence of the PAX3-FOXO1 or PAX7-FOXO1 gene fusions. RMS resembles developing skeletal muscle and has been speculated to originate from genetically compromised skeletal muscle progenitors. Despite the expression of skeletal muscle master regulator proteins MYOD1 and MYOGENIN, RMS tumors and cells fail to terminally differentiate, suggesting that RMS is an arrested state of muscle development. The molecular underpinnings of the differentiation arrest in RMS and therapeutics to drive differentiation are unknown. The long-term goal is to elucidate the mechanisms that determine the basis for developmental arrest in RMS and design novel, directed drug therapies for RMS. A study recently identified PTEN promoter hypermethylation with decrease PTEN expression in over 90% of FN-RMS tumors. In a RMS genetically engineered mouse model (GEMM), PTEN loss decreased tumor latency, increased tumor penetrance, and much less differentiated tumors more closely resembling the embryonal RMS in children. PTEN loss did not increase mTOR signaling but was localized in the nucleus and increased PAX7 expression and ectopic DBX1 expression. DBX1 is a neuronal specific transcriptional repressor that is ectopically expressed across both human FN-RMS and FP-RMS. Forced DBX1 expression blocks myogenic differentiation in cultured myoblasts. The central hypothesis is that the PTEN-PAX7- DBX1 axis provides a key node in the developmental arrest in RMS and that DBX1 functions as a transcriptional repressor blocking differentiation in RMS. The objective of this proposal is to leverage our robust RMS mouse models coupled with in vitro assays to define the role of PTEN and DBX1 in RMS. To accomplish this objective, we propose the following Specific Aims: 1) Define the role of PTEN loss in RMS. 2) Determine the mechanism of DBX1 regulation in RMS. 3) Identify role of DBX1 in blocking myogenic differentiation in RMS. The proposed studies leverage a simple, rapid RMS GEMM to dissect genes that contribute to RMS biology in vivo and provide insight into the mechanism maintaining an arrested state of differentiation in RMS. We will use gain- and loss- of-function approaches both in vivo and in vitro to dissect the roles of AKT1, mTORC1, PAX7 and DBX1 in modulation of the PTEN loss phenotype. Differentiation therapy of embryonal tumors has proven an efficacious venue for therapy with 13-cis-retinoic acid for neuroblastoma and all-trans-retinoic acid for acute promyelocytic leukemia. Molecular and developmental dissection of RMS will reveal new vulnerabilities to develop new therapeutics to drive terminal differentiation of RMS. These studies will have broad impact as DBX1 is highly expressed in pediatric brain tumors and PTEN perturbations are involved in many cancers.

项目总结/文摘