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Understanding Infantile Rhabdomyosarcoma Biology and Therapeutic Targets

了解婴儿横纹肌肉瘤生物学和治疗靶点

基本信息

批准号：
10709542
负责人：
Genevieve Claire Kendall
金额：
$ 37.52万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709542
关键词：
ADP-ribosylation factor 6 Actins Address Affect Allografting Alveolar Rhabdomyosarcoma Animal Model Animals Binding Biochemical Biology Cancer Biology Cancer Model Cell Culture Techniques Cell Line Cell Lineage Cells Child Childhood Chromatin Classification Clinical Complex Data Development Developmental Biology Developmental Gene Disease Embryonal Rhabdomyosarcoma Endocytic Vesicle Event FOXO1A gene Gene Expression Profile Gene Fusion Genetic Genetic Diseases Genetic Transcription Genomics Goals Human Knock-out Knowledge Malignant Childhood Neoplasm Malignant Neoplasms Maps Mediating Modeling Molecular Monomeric GTP-Binding Proteins Mus Muscle Muscle Development Mutation Myoblasts NCOA2 gene Nuclear Receptors Oncogenes Oncogenic Oncology Operative Surgical Procedures PAX3 gene Pathway interactions Patients Predisposition Property Radiation Research Rhabdomyosarcoma Role Sampling Series Skeletal Muscle Structure System Tertiary Protein Structure Testing Therapeutic Transcription Coactivator Transgenic Organisms Validation Zebrafish chemotherapy clinical care clinical sequencing comparative disease-causing mutation druggable target human disease infancy innovation malignant muscle neoplasm mutant myogenesis novel novel therapeutic intervention overexpression patient derived xenograft model progenitor programs side effect small molecule spatiotemporal targeted treatment therapeutic target transcription factor tumor tumor initiation tumorigenesis tumorigenic zebrafish development

项目摘要

PROJECT SUMMARY/ABSTRACT Infantile rhabdomyosarcoma (RMS) is a newly identified and poorly understood aggressive cancer with immature skeletal muscle properties that affects young children. Recent clinical sequencing efforts have identified a spectrum of likely biologically related gene fusions that genetically define infantile RMS: the most common being a fusion between two transcriptional co-activators with roles in normal muscle development, termed VGLL2- NCOA2. Although we know the defining oncogenic event, there are no therapies targeting the genetics of the disease. Thus, patients are treated with general chemotherapy, surgery, and radiation, often ineffectively or with harsh long-term side effects. There is a pressing need to understand the biology of infantile RMS, contextualize infantile RMS biology with other RMS sub-types, and leverage this information to delineate therapeutic targets. Progress is limited by a lack of animal models, cell lines, and PDXs to study the disease dynamics. My long-term goal is to integrate vertebrate zebrafish, mouse, cell culture models and patient samples to identify conserved genetic programs for RMS tumorigenesis and novel therapeutic strategies. Toward that end, this project’s main objective is to elucidate the underlying biology and therapeutic targets in fusion-oncogene driven infantile RMS. Our central hypothesis is that VGLL2-NCOA2 leverages normal developmental programs, including ARF6, to mediate infantile RMS tumorigenesis, and that targeting these pathways is a therapeutic opportunity. Our specific aims will address this hypothesis by: (Aim 1) Delineating VGLL2-NCOA2 structure-function requirements for tumorigenesis, (Aim 2) Establishing mechanisms of VGLL2-NCOA2 and ARF6 cooperation in rhabdomyosarcoma, and (Aim 3) Determining VGLL2-NCOA2 muscle lineage context and temporal prerequisites for tumorigenesis. Completing these studies at the interface of developmental and cancer biology will generate significant new knowledge regarding fusion-oncogene leveraging of developmental programs and will identify potential therapeutic targets. The proposed research is conceptually innovative because it leverages a cross-species comparative oncology approach to pinpoint the most important molecular drivers in a new disease, and it is experimentally innovative because it utilizes multiple new vertebrate (zebrafish and mouse) infantile RMS models developed by our group. Successful execution of this project will generate exciting data focused on delineating the basic biology of infantile rhabdomyosarcoma to directly impact and guide clinical care.

项目摘要/摘要摘要婴儿横纹肌肉瘤(RMS)是一种新发现且知之甚少的未成熟侵袭性癌症。影响幼儿的骨骼肌特性。最近的临床测序工作已经确定了一种从基因上定义婴儿RMS的可能生物相关基因融合的频谱：最常见的是两个在正常肌肉发育中起作用的转录共激活子之间的融合，称为VGLL2- NCOA2。尽管我们知道致癌事件的定义，但目前还没有针对肿瘤遗传学的治疗方法疾病。因此，患者接受全身化疗、手术和放射治疗，通常是无效的或严重的长期副作用。迫切需要了解婴儿RMS的生物学，并将其与背景联系起来婴儿RMS生物学与其他RMS亚型，并利用这些信息来描绘治疗目标。由于缺乏研究疾病动力学的动物模型、细胞系和PDX，进展受到限制。我的长期生活目标是整合脊椎动物斑马鱼、小鼠、细胞培养模型和患者样本，以确定保守的 RMS肿瘤发生的遗传程序和新的治疗策略。为此，这个项目的主要目的阐明融合癌基因驱动的婴幼儿RMS的生物学基础和治疗靶点。我们的中心假设是VGLL2-NCOA2利用包括ARF6在内的正常发育程序来介导婴儿RMS肿瘤的发生，以这些通路为靶点是一个治疗机会。我们的特定 AIMS将通过以下方式解决这一假设：(AIMS 1)描述VGLL2-NCOA2结构-功能要求肿瘤发生，(目的2)建立VGLL2-NCOA2和ARF6协同作用机制横纹肌肉瘤，和(目标3)确定VGLL2-NCOA2肌肉谱系背景和时间肿瘤发生的先决条件。在发育生物学和癌症生物学的交界处完成这些研究将产生关于融合癌基因利用发展项目的重要新知识将确定潜在的治疗靶点。拟议的研究在概念上是创新的，因为它利用了一种跨物种比较肿瘤学的方法，以确定新的疾病，它在实验上是创新的，因为它利用了多种新的脊椎动物(斑马鱼和老鼠) 本课题组研制的婴幼儿RMS模型。该项目的成功实施将产生令人兴奋的数据重点勾勒出婴幼儿横纹肌肉瘤的基本生物学特征，直接影响和指导临床治疗。