MTDH regulates Fanconi anemia repair pathway to mediate drug resistance

MTDH调节范可尼贫血修复途径介导耐药性

• 批准号: 8816751
• 负责人: Kimberly K. Leslie
• 金额: $ 32.7万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-18 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816751
• 关键词: Address; Aftercare; Automobile Driving; Binding; Biomedical Research; Cancer Biology; Cancer Patient; Cancer cell line; Carboplatin; Cell Death; Cells; Chromosomes, Human, Pair 8; Cisplatin; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; DNA Damage; DNA Repair; DNA Repair Pathway; DNA repair protein; Data; Development; Drug resistance; Embryo; Endometrial Carcinoma; Endometrial Neoplasms; Failure; Family; Fanconi' s Anemia; Fibroblasts; Foundations; Future; Gene Expression; Genes; Genetic Translation; Goals; Grant; Gynecologic; Human; Knock-out; Lead; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Mediating; Messenger RNA; Metabolism; Molecular; Mus; Mutation; Neoplasm Metastasis; Oncogenes; Outcome; Pathway interactions; Patients; Phenotype; Post-Transcriptional Regulation; Proteins; Publications; RNA-Binding Proteins; Recurrent disease; Regimen; Regulation; Research; Research Personnel; Resistance; Role; Solid Neoplasm; Specimen; Testing; Therapeutic; Tissues; Translational Regulation; Translations; Treatment Efficacy; Tumor Bank; Tumor Tissue; Work; Xenograft Model; Xenograft procedure; base; cancer risk; cancer therapy; cancer type; chemotherapeutic agent; chemotherapy; expectation; insight; mRNA Stability; member; mimetics; novel; outcome forecast; overexpression; prevent; public health relevance; repaired; research study; response; success; therapy resistant; tumor

DESCRIPTION (provided by applicant): Cellular resistance is one of the major causes of therapeutic failure for solid tumors, thus highlighting the need to identify novel factors driving aggressive phenotypes. Overexpression of metadherin (MTDH, also known as AEG-1 and LYRIC) has been documented in numerous solid tumors to date and correlates with poor prognosis. Moreover, MTDH overexpression has been implicated in metastasis and resistance to therapy, two important hallmarks of an aggressive cancer. We recently made the important discovery that MTDH acts as an RNA binding protein to alter translation of multiple mRNAs, thus identifying a potential role for MTDH in post- translational gene expression. These mRNAs include several DNA repair proteins in the Fanconi anemia (FA) pathway. Our objective in this application is to determine the role of MTDH regulation of DNA repair in resistance to therapy. The rationale for this project is that because MTDH is highly expressed in multiple cancer types and contributes to the emergence of a resistant phenotype, mechanistic insights into how MTDH functions will offer a strong scientific framework whereby MTDH pathway targeted therapies can be developed. To test our central hypothesis, we propose three specific aims: In Aim 1, we will identify mechanisms by which MTDH association with specific mRNAs alters the DNA damage response pathway. Using MTDH-deficient cancer cell lines and MTDH-/- mouse embryonic fibroblasts, we will study the role of MTDH in mRNA metabolism and control of translation of Rad18, FANCI, FANCD2 and other DNA repair proteins. We will extend studies to determine if MTDH knockdown or disruption the MTDH:mRNA complex by mRNA mimetics are sufficient to perturb MTDH translational regulation of FA pathway genes. In Aim 2, we will overcome resistance to cisplatin by targeting MTDH and the DNA repair pathway. We will evaluate whether targeting MTDH and the FA DNA repair pathway can increase the therapeutic efficacy of cisplatin via disruption of the cellular response to DNA damage. In Aim 3, we will determine the effect of MTDH expression and FA pathway activation on resistance to ICL-inducing agents in cancer. Studies will include 1) xenograft experiments using well-characterized human endometrial tumors from our viable tumor bank; and 2) immunohistochemical analysis of the MTDH and FA pathway in FFPE tumor tissues from 86 advanced endometrial cancer patients treated with ICL-inducing agents. Upon the successful completion of the proposed research, it is our expectation that we will understand the pathological function of MTDH through its regulation of mRNA stability and translation of FA pathway proteins. These results are expected to have an important positive impact because they will provide a strong mechanistic basis for the correlation of MTDH overexpression with therapeutic resistance and serve as a foundation for the future development of MTDH-targeted therapies.

描述（由申请人提供）：细胞耐药性是实体瘤治疗失败的主要原因之一，因此强调需要鉴定驱动侵袭性表型的新因素。迄今为止，已在许多实体瘤中记录到麦粘蛋白（MTDH，也称为 AEG-1 和 LYRIC）的过度表达，并且与不良预后相关。此外，MTDH 过度表达与转移和治疗耐药有关，这是侵袭性癌症的两个重要标志。我们最近做出了重要发现，MTDH 作为 RNA 结合蛋白来改变多个 mRNA 的翻译，从而确定了 MTDH 在翻译后基因表达中的潜在作用。这些 mRNA 包括范可尼贫血 (FA) 途径中的几种 DNA 修复蛋白。我们本申请的目的是确定 MTDH 调节 DNA 修复在治疗耐药中的作用。该项目的基本原理是，由于 MTDH 在多种癌症类型中高度表达，并导致耐药表型的出现，因此对 MTDH 功能的机制了解将提供强大的科学框架，从而开发 MTDH 途径靶向治疗。为了检验我们的中心假设，我们提出了三个具体目标：在目标 1 中，我们将确定 MTDH 与特定 mRNA 的关联改变 DNA 损伤反应途径的机制。使用MTDH缺陷型癌细胞系和MTDH-/-小鼠胚胎成纤维细胞，我们将研究MTDH在mRNA代谢和控制Rad18、FANCI、FANCD2和其他DNA修复蛋白翻译中的作用。我们将扩展研究以确定 MTDH 敲低或通过 mRNA 模拟物破坏 MTDH:mRNA 复合物是否足以扰乱 FA 途径基因的 MTDH 翻译调节。在目标 2 中，我们将通过靶向 MTDH 和 DNA 修复途径来克服对顺铂的耐药性。我们将评估靶向 MTDH 和 FA DNA 修复途径是否可以通过破坏细胞对 DNA 损伤的反应来提高顺铂的治疗效果。在目标 3 中，我们将确定 MTDH 表达和 FA 通路激活对癌症中 ICL 诱导剂耐药性的影响。研究将包括 1) 使用来自我们可行的肿瘤库的特征良好的人类子宫内膜肿瘤进行异种移植实验； 2) 对 86 例接受 ICL 诱导剂治疗的晚期子宫内膜癌患者的 FFPE 肿瘤组织中的 MTDH 和 FA 通路进行免疫组织化学分析。在成功完成拟议的研究后，我们期望我们能够通过 MTDH 对 mRNA 稳定性和 FA 途径蛋白翻译的调节来了解其病理功能。这些结果预计将产生重要的积极影响，因为它们将为 MTDH 过表达与治疗耐药的相关性提供强有力的机制基础，并为未来开发 MTDH 靶向疗法奠定基础。