Dissecting and Targeting RB1-Mutant Osteosarcoma

剖析和靶向 RB1 突变骨肉瘤

基本信息

批准号：
10746741
负责人：
Dung-Fang Lee
金额：
$ 40.48万
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/10746741
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 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 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 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 Variant anticancer research autosome bone cancer genetics chemotherapy clinical application disorder control exome sequencing experimental study genome-wide analysis human disease human model improved in vitro Model induced pluripotent stem cell inhibitor insight leukemia mortality multicatalytic endopeptidase complex mutant new therapeutic target novel novel therapeutic intervention osteosarcoma pharmacologic 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.

项目概要/摘要骨癌是儿童和青少年最常见的原发恶性肿瘤之一。骨肉瘤几乎占骨肉瘤常见组织学亚型的 60%。虽然五年生存率非转移性疾病徘徊在大约 70%，转移性疾病（最常见的是肺部）与存活率为15%至30%。尽管手术和多药化疗取得了进展，但仍缺乏对骨肉瘤发生分子机制的了解阻碍了骨肉瘤发生的显着改善过去40年患者的生存情况。这种恶性肿瘤使骨肉瘤成为主要原因之一儿童和青少年的癌症死亡率。因此，阐明个体的功能骨肉瘤相关基因（如RB1和p53抑癌基因）探索可能的病理机制骨肉瘤发生、发展和进展的机制对于未来骨肉瘤至关重要检测和治疗。诱导多能干细胞（iPSC）是癌症公认的最有前途的平台之一研究人员。最近，包括我们在内的多个团队成功地将患者来源的 iPSC 应用于表型癌症特征、探索疾病机制、筛选治疗药物。这些发现强烈表明患者—— 衍生的 iPSC 是建模和剖析癌症病因学的可行系统。遗传性视网膜母细胞瘤患者 (RB)，一种遗传性常染色体显性癌症，由 RB1 肿瘤种系突变/缺失引起抑制基因，使骨肉瘤的发病率增加了 400 倍以上，这提供了一个完美的模型系统研究RB1在骨肉瘤发生中的作用。我们的初步研究表明，RB iPSC 衍生的成骨细胞中剪接体基因有所增加。这些结果引出了我们的中心假设，即剪接体功能的改变对于促进肿瘤发生很重要 RB1 突变骨肉瘤的发生和发展。在强有力的初步数据的指导下，我们计划利用 RB 源自患者的 iPSC 疾病模型旨在追求三个具体目标以阐明病理机制参与 RB1 突变骨肉瘤：(1) 阐明 RB1 缺失如何导致剪接体上调基因表达。 (2)评估剪接调节剂治疗骨肉瘤的潜力。 (3) 明确 CUL9 在调节 RB1 功能中的作用。总的来说，我们提出的研究将通过表征骨肉瘤领域来广泛影响骨肉瘤领域剪接体在调节 RB1 突变骨肉瘤发展中的重要作用。这些研究还将有有可能揭示由 CUL9 肿瘤控制的调节 RB1 蛋白水解的新分子机制抑制器。成功完成拟议的实验将为广泛的研究增添有价值和新颖的见解一系列领域，包括癌症遗传学、剪接体基因表达失调和泛素蛋白酶体蛋白水解途径，每个途径都具有骨肉瘤治疗的潜在临床应用。