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Dissecting and Targeting RB1-Mutant Osteosarcoma

剖析和靶向 RB1 突变骨肉瘤

基本信息

批准号：
10358587
负责人：
Dung-Fang Lee
金额：
$ 42.08万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10358587
关键词：
Achievement Adolescence Adolescent Affect Alternative Splicing Binding Biological Markers Biological Models Brain Neoplasms CRISPR/Cas technology CUL9 gene Cancer Etiology Cells ChIP-seq Child Clinical Data Deletion Mutation Detection Development Disease Disease model Down-Regulation Etiology Fibroblasts Future Gene Expression Genes Genetic Genome Germ-Line Mutation Goals Hereditary Retinoblastoma Histologic Human Impairment Incidence Individual Inherited Knockout Mice Lead Li-Fraumeni Syndrome Link Lung Malignant Bone Neoplasm Malignant Childhood Neoplasm Malignant Neoplasms Mediating Methodology Missense Mutation Modeling Molecular Mus Mutation Non-Hematologic Malignancy Nonmetastatic Operative Surgical Procedures Osteoblasts Pathologic Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenocopy Proteins Proteolysis RB1 gene RNA Splicing Research Research Personnel Retinoblastoma Role Specimen Spliceosomes Survival Rate System TP53 gene Technology Testing Therapeutic Tumor Suppressor Genes Tumor Suppressor Proteins Ubiquitin Ursidae Family Variant anticancer research bone cancer genetics chemotherapy clinical application disorder control exome sequencing experimental study genome-wide analysis human disease human model in vitro Model induced pluripotent stem cell inhibitor insight leukemia mortality multicatalytic endopeptidase complex mutant new therapeutic target novel novel therapeutic intervention osteosarcoma precise genome editing prevent promoter transcriptome tumor initiation ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY/ABSTRACT Bone cancer is one of the most common primary malignancies in children and adolescents. Osteosarcoma comprises almost 60% of the common histological subtypes of bone sarcoma. While the five-year survival rate of non-metastatic disease hovers at approximately 70%, metastatic disease, most often to the lungs, is associated with survival rates of 15% to 30%. Despite advances in surgery and multi-agent chemotherapy, lack of understanding of the molecular mechanisms of osteosarcomagenesis has prevented significant improvement in the survival of patients over the past 40 years. This malignancy makes osteosarcoma one of the leading causes of cancer mortality among children and adolescents. Therefore, elucidation of the function of individual osteosarcoma-associated genes (e.g., RB1 and p53 tumor suppressor genes) to explore the possible pathological mechanisms involved in osteosarcoma initiation, development and progression is critical for future osteosarcoma detection and treatment. Induced pluripotent stem cells (iPSCs) is one of the most promising platforms recognized by cancer researchers. Recently, several groups including us successfully apply patient-derived iPSCs to phenocopy cancer features, explore disease mechanisms, and screen therapeutic drugs. These findings strongly suggest patient- derived iPSCs is a feasible system to model and dissect cancer etiology. Patients with hereditary retinoblastoma (RB), an inherited autosomal dominant cancer disorder caused by germline mutations/deletions in the RB1 tumor suppressor gene, have increased >400 fold incidence of osteosarcoma, which provides a perfect model system to study the role of RB1 in osteosarcomagenesis. Our preliminary studies revealed that an increase of spliceosome genes in RB iPSC-derived osteoblasts. These results lead to our central hypothesis that an altered spliceosome function is important for facilitating tumor initiation and development in RB1-mutant osteosarcoma. Guided by strong preliminary data, we plan to utilize RB patient-derived iPSC disease model to pursue three Specific Aims to elucidate the pathological mechanisms involved in RB1-mutant osteosarcoma: (1) To elucidate how loss of RB1 contributes to upregulated spliceosome gene expression. (2) To evaluate the therapeutic potential of splicing modulators for osteosarcoma treatment. (3) To define the role of CUL9 in regulating RB1 function. Collectively, our proposed research will broadly impact the osteosarcoma field by characterizing the essential role of spliceosome in regulating RB1-mutant osteosarcoma development. These studies will also have potential to uncover novel molecular mechanisms regulating RB1 proteolysis controlled by CUL9 tumor suppressor. Successful completion of the proposed experiment will add valuable and novel insights to a broad range of fields including cancer genetics, dysregulation of spliceosome gene expression, and ubiquitin- proteasome proteolytic pathway, each of which bears potential clinical applications for osteosarcoma treatment.

项目总结/文摘