The Dependency on MYOD for Growth in Rhabdomyosarcoma

横纹肌肉瘤生长对 MYOD 的依赖性

• 批准号: 10364634
• 负责人: Cristian Ryan Cleary
• 金额: $ 4.09万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-16 至 2025-03-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364634
• 关键词: BHLH Protein; Binding; Biological Assay; CRISPR interference; Cancer cell line; Caring; Cell Line; Cells; ChIP-seq; Childhood; Complementary DNA; Dactinomycin; Data; Data Set; Dependence; Diagnosis; Disadvantaged; Disease; Drug toxicity; Environment; Failure; Family; Foundations; Functional disorder; Future; Genes; Genetic; Genetic Screening; Genetic Transcription; Goals; Growth; Helix-Turn-Helix Motifs; Incidence; Investigation; Knock-out; Knowledge; Laboratories; Light; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Medical; Mentorship; Molecular; Muscle; Muscle Fibers; Neoplasms; Pathway interactions; Patients; Phenotype; Population; Regulation; Research; Research Proposals; Resolution; Resources; Rhabdomyosarcoma; Role; Scientist; Skeletal Myoblasts; Solid Neoplasm; Stains; Survival Rate; Systemic Therapy; Therapeutic; Toxic effect; Training Programs; United States; Universities; Vincristine; anticancer research; chemotherapy; clinical care; clinical diagnosis; differential expression; experimental study; fitness; functional genomics; genetic selection; insight; member; morphogens; myogenesis; novel strategies; novel therapeutics; pediatric patients; programs; science education; skills; small molecule inhibitor; standard of care; targeted treatment; transcription factor; transcriptome sequencing; tumor; tumor growth

Project Summary Rhabdomyosarcoma (RMS) is the most common extra-cranial solid tumor in the pediatric population of the United States by incidence. RMS is a high-grade neoplasm composed of cells that resemble skeletal myoblasts and express some markers of myogenic differentiation but do not form functional myotubes. The standard systemic therapy for RMS consists of intensive multi-agent chemotherapy and has not significantly changed in nearly five decades. These compounds target general vulnerabilities of rapidly dividing cells and are not specific to the pathophysiology of RMS. As such, treatment is accompanied by a suite of toxicities with potentially lifelong repercussions in pediatric patients. Approximately 20% of RMS patients present with metastatic disease at diagnosis, and the failure-free survival rate for these patients is only 30% after five years. Hence, there is a pressing need for specific yet potent therapies for RMS. High-throughput, negative-selection genetic screens across cell lines of varying tumor types have the potential to reveal growth dependencies specific to a given cancer. Our results from these functional genomics experiments identified myogenic differentiation 1 (MYOD) as the most potent growth dependency factor specific to RMS. MYOD is a member of the basic Helix-Loop-Helix family of transcription factors and is a master regulator of muscle differentiation. MYOD is one of the predominant myogenic markers used in the clinical diagnosis of RMS but has long been thought to be functionally inactive in RMS, as this cancer does not complete the myogenic differentiation program. However, in light of our genetic screening data, we hypothesize that RMS exploits the transcriptional activity of MYOD to drive growth of the tumor. The proposed research aims to determine the molecular mechanisms by which MYOD regulates growth of RMS. The outlined experiments will identify features of MYOD necessary for sustaining RMS growth (Aim 1), uncover the genetic targets of MYOD that mediate growth (Aim 2), and evaluate the functional significance of MYOD targets (Aim 3). Data from these experiments will provide insight into the molecular pathophysiology of RMS and may reveal critical nodes in this program that warrant therapeutic investigation. The requisite skills and knowledge to carry out this research proposal will be supported by the integrated basic and medical science education in the Medical Scientist Training Program at Stony Brook University (SBU). The mentorship and environments at SBU and Cold Spring Harbor Laboratory will provide all of the necessary resources for a tailored training program to effectively develop the applicant into an independent experimentalist, analyst, and communicator of cancer research.

项目摘要 横纹肌肉瘤（RMS）是最常见的颅外实体瘤的儿童人口的 美国的发病率RMS是一种高度恶性肿瘤，由类似骨骼肌成肌细胞的细胞组成， 表达肌源性分化的一些标志物，但不形成功能性肌管。标准的全身治疗 RMS的治疗包括强化的多药化疗，近五十年来没有显著变化。这些 这些化合物针对快速分裂细胞的一般脆弱性，并且不是RMS的病理生理学特异性的。作为 这样的治疗伴随着一系列毒性，对儿科患者具有潜在的终身影响。 大约20%的RMS患者在诊断时存在转移性疾病， 这些病人在五年后只有30%因此，迫切需要针对RMS的特异性但有效的疗法。 在不同肿瘤类型的细胞系中进行高通量、负选择遗传筛选， 揭示特定癌症的生长依赖性。我们从这些功能基因组学实验中发现， 肌原性分化1（MYOD）是RMS特异性的最有效的生长依赖因子。MYOD是会员 是基本的螺旋-环-抑制因子家族的转录因子，是肌肉分化的主要调节因子。MYOD是 它是临床诊断RMS的主要肌源性标志物之一，但长期以来一直被认为是 在RMS中功能不活跃，因为这种癌症没有完成肌源性分化程序。但鉴于 根据我们的遗传筛选数据，我们假设RMS利用MYOD的转录活性来驱动 肿瘤该研究旨在确定MYOD调节RMS生长的分子机制。 概述的实验将确定维持RMS增长所需的MYOD特征（目标1）， MYOD介导生长的遗传靶点（目的2），并评估MYOD靶点的功能意义（目的 3）。这些实验的数据将为RMS的分子病理生理学提供深入的了解，并可能揭示关键的 需要进行治疗性研究的节点 开展这项研究计划所需的技能和知识将得到综合基础知识的支持。 在斯托尼布鲁克大学（SBU）的医学科学家培训计划中进行医学科学教育。的 SBU和冷泉港实验室的指导和环境将为一个 量身定制的培训计划，以有效地发展申请人成为一个独立的实验，分析师， 癌症研究的传播者。