The Dependency on MYOD for Growth in Rhabdomyosarcoma

项目摘要 横纹肌肉瘤(RMS)是儿童最常见的颅外实体瘤。 美国的发病率。RMS是一种高级别肿瘤，由类似骨骼肌母细胞的细胞组成， 表达一些肌源性分化的标志，但不形成功能性肌管。标准的系统疗法 对于RMS来说，包括密集的多药剂化疗，近50年来没有显著变化。这些 化合物针对快速分裂细胞的一般脆弱性，并不是RMS的病理生理学所特有的。AS 这样的治疗伴随着一系列毒性反应，可能会对儿科患者产生终身影响。 大约20%的RMS患者在确诊时存在转移性疾病， 这些患者五年后只有30%。因此，迫切需要针对RMS的特效而有效的治疗方法。 在不同肿瘤类型的细胞系中进行高通量、负选择的基因筛查有可能 揭示特定癌症特有的生长依赖关系。我们从这些功能基因组学实验中得到的结果证明 肌源性分化1(MYOD)是RMS特异性最强的生长依赖因子。MYOD是会员 属于基本的螺旋-环-螺旋转录因子家族，是肌肉分化的主要调节因子。MYOD是 RMS临床诊断中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，因为这种癌症不完成肌源性分化程序。然而，鉴于 我们的基因筛选数据，我们假设RMS利用MYOD的转录活性来驱动 肿瘤。这项研究旨在确定MYOD调控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)，揭示 MYOD调节生长的遗传靶标(AIM 2)，并评估MYOD靶标的功能意义(AIM 3)。这些实验的数据将提供对RMS的分子病理生理学的洞察，并可能揭示关键的 该计划中需要进行治疗性研究的节点。 执行这项研究提案所需的技能和知识将得到综合基础设施的支持 以及石溪大学(SBU)医学科学家培训计划中的医学教育。这个 SBU和冷泉港实验室的指导和环境将提供所有必要的资源 量身定制的培训计划，以有效地将申请者发展为独立的实验者、分析员和 癌症研究的传播者。

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.