Understanding Infantile Rhabdomyosarcoma Biology and Therapeutic Targets

了解婴儿横纹肌肉瘤生物学和治疗靶点

• 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
• 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

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 婴儿横纹肌肉瘤（RMS）是一种新发现的，侵略性较低，侵略性癌症未成熟 影响幼儿的骨骼肌特性。最近的临床测序工作已经确定 通常定义基础设施RMS的可能与生物学相关的基因融合频谱：最常见的是 两个转录共激活因子在正常肌肉发育中作用的融合，称为VGLL2- NCOA2。尽管我们知道定义的致癌事件，但没有针对遗传学的疗法 疾病。这就是患者接受一般化疗，手术和放射线治疗，通常是无效或与 严格的长期副作用。迫切需要了解基础架构RMS的生物学，上下文化 使用其他RMS子类型的婴儿RMS生物学，并利用这些信息来描述治疗靶标。 进步受动物模型，细胞系和PDX缺乏来研究疾病动态的限制。我的长期 目标是整合脊椎动物斑马鱼，小鼠，细胞培养模型和患者样品以识别保守的 RMS肿瘤发生和新型治疗策略的遗传程序。为此，这个项目的主要 目的是阐明融合 - 癌基因驱动基础设施RMS中的基本生物学和治疗靶标。 我们的中心假设是，VGLL2-NCOA2利用包括ARF6在内的正常发展计划 介导婴儿RMS肿瘤发生，靶向这些途径是一种治疗机会。我们的具体 目标将通过：（目标1）划定VGLL2-NCOA2结构功能的要求 肿瘤发生（AIM 2）建立VGLL2-NCOA2和ARF6合作的机制 横纹肌肉瘤和（AIM 3）确定VGLL2-NCOA2肌肉谱系和临时性 肿瘤发生的先决条件。在发育和癌症生物学的界面上完成这些研究 关于发展计划的融合 - 缔合率和 将确定潜在的治疗靶标。拟议的研究在概念上是创新的，因为它利用了 跨物种比较肿瘤学方法，以查明新的分子驱动器 疾病，它在实验上是创新的，因为它利用了多种新脊椎动物（斑马鱼和小鼠） 我们小组开发的婴儿RMS模型。该项目的成功执行将产生令人兴奋的数据 专注于描述基础设施横纹肌肉瘤的基本生物学，以直接影响和指导临床护理。

项目成果

A Robust Closed-Tube Method for Resolving tp53M214K Genotypes.

用于解析 tp53M214K 基因型的稳健闭管方法。

• DOI: 10.1089/zeb.2023.0030
• 发表时间: 2024
• 期刊: Zebrafish
• 影响因子: 2
• 作者: Silvius,KatherineM;Kendall,GenevieveC
• 通讯作者: Kendall,GenevieveC

VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis.

• DOI: 10.1016/j.celrep.2023.112013
• 发表时间: 2023-01-31
• 期刊: Cell reports
• 影响因子: 8.8