Elucidating the survival mechanisms of rhabdomyosarcoma

阐明横纹肌肉瘤的生存机制

基本信息

批准号：
10595553
负责人：
Alexander R. Oles
金额：
$ 4.98万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10595553
关键词：
Affect Apoptotic Belief Bioinformatics Biology Carcinoma Cell Death Cell Survival Cells Cessation of life Child Classification Compensation CpG Islands DNA Binding DNA Modification Methylases DNMT3a Data Decitabine Defect Diagnosis Disease Exposure to FDA approved Family Focus Groups Functional disorder Genes Genotoxic Stress Goals Hematologic Neoplasms Histologic Hypermethylation In Vitro Induction of Apoptosis Laboratories Malignant Childhood Neoplasm Malignant Neoplasms Mesenchymal Methylation Myf-6 myogenic factor MyoD Protein Myogenic Regulatory Factors Myogenin Neoplasm Metastasis Oncogenes Oncologist Operative Surgical Procedures Patients Pharmaceutical Preparations Phenotype Promoter Regions Proteins Protocols documentation Radiation Recurrence Refractory Regulation Rhabdomyosarcoma Role Series Signal Pathway Skeletal Muscle Stress Survival Rate Techniques Testing The Cancer Genome Atlas Therapeutic Tumor Promotion Undifferentiated cancer cell cancer classification cell killing chemotherapy combinatorial cytotoxic demethylation efficacy testing experience experimental study gain of function improved inhibitor loss of function myogenesis neoplastic cell new therapeutic target next generation sequencing novel novel therapeutic intervention preclinical study programs promoter response sarcoma skeletal muscle differentiation soft tissue standard of care therapeutic target transcription factor transcriptomics treatment strategy tumor tumor xenograft tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Rhabdomyosarcoma (RMS) is the most common soft tissue cancers affecting children. Despite aggressive combinatorial therapy, nearly 30% of children diagnosed with RMS will succumb to either metastasis or recurrence. While RMS can occur anywhere in the body, all cases are defined by the expression of skeletal muscle markers. Skeletal muscle differentiation is controlled by a family of four DNA binding myogenic regulatory factors - MyoD, Myf5, myogenin and MRF4. The prevailing belief is that RMS tumor cells are unable to complete differentiation due to the dysfunction of these myogenic factors. Our laboratory previously showed that NF-κB contributes to RMS by maintaining tumor cells in an undifferentiated state. Interestingly, even though NF-κB is widely known to function in cancer as a survival factor, RMS appears to be unique in not needing NF-κB to overcome stress-induced apoptosis. Instead, we find that MyoD is able to compensate for NF-κB. One mechanism by which MyoD promotes survival is by keeping RMS cells in a partially differentiated state. Another mechanism, which we elucidated through a series of transcriptomic and bioinformatic analyses, indicates that MyoD is capable of suppressing apoptotic genes. Unique to this latter mechanism is that suppression requires promoter methylation. Based on these data, I hypothesize that MyoD functions in RMS by acting as an oncogene to promote cell survival, which occurs by 1) maintaining RMS cells in a partially differentiated state and 2) suppressing apoptotic genes through the regulation of DNMTs and promoter hypermethylation. The second part of this hypothesis will be explored in this proposal through two aims. In Aim 1, I plan to characterize the pro- apoptotic genes suppressed by MyoD and their relevance in RMS. I will accomplish this through gain and loss of function studies for each gene and observing the death response phenotype. I will also explore the methylation of the gene promoters in response to MyoD expression or treatment with compounds that regulate methylation. In Aim 2, I will perform preclinical studies to test the efficacy of demethylation agents as a therapeutic strategy in RMS. Both in vitro and xenograft tumor studies will be utilized, using demethylation agents alone or in combination with RMS standard of care drugs. The impact of my findings might not only demonstrate a novel role of MyoD in RMS, but might also advance novel therapeutic strategy for the treatment of RMS patients.

项目概要/摘要横纹肌肉瘤 (RMS) 是影响儿童的最常见的软组织癌症，尽管具有侵袭性。联合治疗中，近 30% 被诊断患有 RMS 的儿童将死于转移或虽然 RMS 可以发生在身体的任何部位，但所有病例均由骨骼的表达来定义。肌肉标记物由四个 DNA 结合肌源性调节因子家族控制。因素 - MyoD、Myf5、肌细胞生成素和 MRF4 人们普遍认为 RMS 肿瘤细胞无法完成分化。由于这些生肌因子的功能障碍而导致的分化。我们的实验室之前表明 NF-κB。通过维持肿瘤细胞处于未分化状态来促进 RMS。众所周知，RMS 是癌症中的一种生存因子，但它的独特之处在于不需要 NF-κB 相反，我们发现 MyoD 能够补偿 NF-κB。 MyoD 促进存活的机制是保持 RMS 细胞处于部分分化状态。我们通过一系列转录组学和生物信息学分析阐明了这一机制，表明 MyoD 能够抑制凋亡基因，后一种机制的独特之处在于抑制需要。基于这些数据，我敢说 MyoD 在 RMS 中发挥癌基因的作用。促进细胞存活，这通过 1) 维持 RMS 细胞处于部分分化状态和 2) 通过调节DNMT和启动子高甲基化来抑制凋亡基因第二部分。在本提案中，我将通过两个目标来探讨这一假设。在目标 1 中，我计划描述亲的特征。 MyoD 抑制的凋亡基因及其与 RMS 的相关性我将通过增益和损失来实现这一点。我还将探索每个基因的功能研究并观察死亡反应表型。基因启动子响应 MyoD 表达或用该化合物调节甲基化的处理。在目标 2 中，我将进行临床前研究，以测试去甲基化药物作为治疗策略的功效在 RMS 中，将使用单独或联合使用去甲基化药物的体外和异种移植肿瘤研究。与 RMS 标准护理药物相结合我的研究结果的影响可能不仅证明了一种新颖的方法。 MyoD 在 RMS 中的作用，但也可能推进治疗 RMS 患者的新治疗策略。