Elucidating the survival mechanisms of rhabdomyosarcoma

阐明横纹肌肉瘤的生存机制

• 批准号: 10464404
• 负责人: Alexander R. Oles
• 金额: $ 4.89万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 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/10464404
• 关键词: Affect; Apoptosis; Apoptotic; Belief; Bioinformatics; Biology; Carcinoma; Cell Death; Cell Survival; Cells; Cessation of life; Child; Classification; CpG Islands; DNA Binding; DNA Modification Methylases; Data; Decitabine; Defect; Diagnosis; Disease; Exposure to; FDA approved; Family; Focus Groups; Functional disorder; Genes; Genotoxic Stress; Goals; Hematologic Neoplasms; Histologic; Hypermethylation; In Vitro; Laboratories; Lead; 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; Undifferentiated; base; cancer cell; cell killing; chemotherapy; combinatorial; cytotoxic; demethylation; efficacy testing; experience; experimental study; 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

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.

项目总结/摘要 横纹肌肉瘤（RMS）是影响儿童的最常见的软组织癌症。尽管进行了积极 联合治疗，近30%的儿童诊断为RMS将死于转移或 复发虽然RMS可以发生在身体的任何地方，但所有病例都是由骨骼肌的表达来定义的。 肌肉标记骨骼肌分化受四个DNA结合肌原性调节因子家族控制 这些因子包括MyoD、Myf 5、肌细胞生成素和MRF 4。普遍认为RMS肿瘤细胞无法完成 由于这些肌原性因子的功能障碍而导致分化。本实验室先前研究表明，NF-κB 通过维持肿瘤细胞处于未分化状态而促成RMS。有趣的是，尽管NF-κB是 众所周知，RMS在癌症中作为一种生存因子发挥作用，它似乎是独特的，不需要NF-κB， 克服应激诱导的细胞凋亡。相反，我们发现MyoD能够补偿NF-κB。一 MyoD促进存活的机制是通过保持RMS细胞处于部分分化状态。另一 我们通过一系列转录组学和生物信息学分析阐明的机制表明， 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 启动子甲基化基于这些数据，我假设MyoD在RMS中作为癌基因发挥作用 促进细胞存活，其通过1）维持RMS细胞处于部分分化状态和2） 通过调节DNMT和启动子超甲基化抑制凋亡基因。第二部分 本提案将通过两个目标探讨这一假设。在目标1中，我计划描述亲- MyoD抑制的凋亡基因及其在RMS中的相关性。我将通过得失来完成这件事 对每个基因进行功能研究并观察死亡反应表型。我还将探索甲基化 基因启动子对MyoD表达或用调节甲基化的化合物处理的响应。 在目标2中，我将进行临床前研究，以测试去甲基化剂作为治疗策略的有效性 在RMS中。将利用体外和异种移植肿瘤研究，单独使用去甲基化剂或与去甲基化剂联合使用。 与RMS标准治疗药物组合。我的发现的影响可能不仅仅是证明一部小说 MyoD在RMS中的作用，但也可能为RMS患者的治疗提出新的治疗策略。