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.

项目摘要/摘要 横纹肌肉瘤（RMS）是影响儿童的最常见的软组织癌。尽管有进取心 组合疗法，将近30％的被诊断为RMS的儿童屈服于转移或 复发。虽然RMS可以发生在体内任何地方，但所有情况均由骨骼的表达来定义 肌肉标记。骨骼肌的分化受四个DNA结合肌源性调节的家族控制 因素 - myod，myf5，肌根蛋白和MRF4。普遍的信念是RMS肿瘤细胞无法完成 由于这些肌源性因素的功能障碍引起的分化。我们的实验室先前表明NF-κB 通过将肿瘤细胞保持在未分化状态下，从而促进RMS。有趣的是，即使NF-κB是 RMS在不需要NF-κB的情况下似乎是癌症作为生存因子的众所周知的，它似乎是独一无二的 克服压力诱导的凋亡。相反，我们发现MYOD能够补偿NF-κB。一 MYOD促进生存的机制是将RMS细胞保持在部分分化状态。其他 我们通过一系列转录组和生物信息学分析阐明了机制，表明 Myod能够抑制凋亡基因。以后的机制独有的是抑制需要 启动子甲基化。基于这些数据，我假设MYOD通过充当癌基因在RMS中的功能 为了促进细胞存活，通过1）在部分分化的状态下维持RMS细胞和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 该假设将通过两个目标在本提案中进行探讨。在AIM 1中，我计划表征 MYOD抑制凋亡基因及其在RMS中的相关性。我将通过收益和损失来实现这一目标 每个基因的功能研究并观察死亡反应表型。我还将探索甲基化 基因启动子响应于Myod表达或用调节甲基化的化合物处理的响应。 在AIM 2中，我将进行临床前研究，以测试脱甲基化剂的效率作为治疗策略 在RMS中。仅使用脱甲基化剂或在体外和异种移植肿瘤研究 与RMS护理药物的结合。我的发现的影响不仅表现出小说 Myod在RMS中的作用，但也可能会推进RMS患者治疗的新型治疗策略。