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Characterizing Chromatin Remodeling Mechanisms of Chemo-Sensitivity and Resistance in Pediatric Solid Tumors

表征儿科实体瘤化疗敏感性和耐药性的染色质重塑机制

基本信息

批准号：
10407079
负责人：
Maggie Chasse
金额：
$ 9.7万
依托单位：
BOSTON CHILDREN'S 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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10407079
关键词：
Address Adult Alveolar Rhabdomyosarcoma Automobile Driving Biochemical Biochemistry Cell Proliferation Cells Chemoresistance Childhood Solid Neoplasm Chimeric Proteins Chromatin Chromatin Remodeling Factor Chromatin Structure Clinical Colorectal Cancer Combination Drug Therapy Combined Modality Therapy Complex DNA Binding Domain DNA Damage DNA Minor Groove Binding Data Disease Drug Screening Epigenetic Process FOXO1A gene Fellowship Frequencies Genetic Transcription Genome Genomic approach Genomics Goals High-Throughput Nucleotide Sequencing Human Investigation Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mass Spectrum Analysis Mutation Oncogenes Oncogenic PAX3 gene Pathway interactions Penetrance Pharmacology Phase Play Plicamycin Population Refractory Relapse Research Residual state Resistance Resistance profile Rhabdoid Tumor Rhabdomyosarcoma Role SMARCB1 gene Solid Neoplasm Somatic Mutation Therapeutic Training Transgenic Model career chemotherapeutic agent chemotherapy childhood sarcoma chromatin remodeling crosslink effective therapy epigenome epigenomics histone demethylase in vivo in vivo Model inhibitor mithramycin A mouse model new therapeutic target novel novel therapeutics resistance mechanism response restoration small molecule therapeutic target therapy resistant transcription factor transcriptomics treatment response tumor

项目摘要

PROJECT SUMMARY Despite the known roles of chromatin remodeling complexes in driving more than 20% of human cancer, the role of chromatin remodeling complexes in conferring therapeutic response in pediatric solid tumors is much less understood. Rhabdoid tumor requires residual SWI/SNF activity for transformation and progression. However, it is not known if SWI/SNF and its effect on the underlying epigenome is therapeutically targetable and if a compound targeting this complex will be successful. Furthermore, SWI/SNF has been implicated in epigenetic mechanisms of resistance suggesting this complex may be able to both confer sensitivity and resistance depending on the cancer context. Fusion positive alveolar rhabdomyosarcoma (ARMS) gains chemo-resistance without the simultaneous gain of mutations to drive this resistance. These data indicate ARMS relapse may be driven by epigenetic mechanisms. Therefore, the overall objective of this study is to define the role of chromatin structure in conferring therapeutic sensitivity in rhabdoid tumor (Aim 1) and resistance in rhabdomyosarcoma (Aim 2). I have identified mithramycin as a SWI/SNF inhibitor that induces epigenetic reprogramming and durable tumor regression in rhabdoid tumor. A consequence of mithramycin treatment is amplification of H3K27me3, a novel therapeutic vulnerability as well as the restoration of chemosensitivity. The overall goal of the F99 phase (Aim 1) is to identify synthetic lethalities that arise from SWI/SNF inhibition. Specifically, aim 1.1 will define inhibition of H3K27me3 histone demethylases KDM6A/6B as a therapeutic vulnerability in rhabdoid tumor. Aim 1.2 will define the mechanism of mithramycin-dependent chemosensitivity. These goals will build advanced expertise in mechanistic pharmacology, high-throughput sequencing, and in vivo modeling of combination therapies. In contrast to RT which is known to be chemo-refractory, alveolar rhabdomyosarcoma is initially responsive to chemotherapy before gaining resistance. Therefore, the K00 phase of this fellowship (Aim 2) will define the role of chromatin remodeling in fusion positive alveolar rhabdomyosarcoma therapeutic resistance (ARMS). Aim 2.1 will identify the chromatin remodeler that coordinates with PAX3/7-FOXO1, the oncogenic transcription factor that drives ARMS transformation and progression. Aim 2.2 will profile chromatin remodeling during the establishment of chemoresistance in an established ARMS mouse model. This phase will expand expertise in genomic approaches to include single-cell genomics and in vivo modeling to include transgenic models. In summary, this study addresses the need for a mechanistic investigation into the role of chromatin remodeling in driving therapeutic response in pediatric solid tumors. Data and training acquired in this phase will prepare me for a career exploring epigenetic mechanisms of therapeutic resistance in pediatric sarcomas.

项目总结