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: 9331485
• 负责人: Kimberly K. Leslie
• 金额: $ 31.36万
• 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/9331485
• 关键词: Address; Aftercare; Alpha Cell; Automobile Driving; Binding; Biomedical Research; CRISPR/Cas technology; Cancer Biology; Cancer Model; Cancer Patient; Cancer cell line; Carboplatin; Cell Death; Cells; Chromosomes, Human, Pair 8; Cisplatin; Clinical; Clinical Trials; Complex; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Pathway; Data; Development; Drug resistance; Embryo; Endometrial Carcinoma; Endometrial Neoplasms; Failure; Family; Fanconi Anemia pathway; Fanconi' s Anemia; Fibroblasts; Foundations; Future; Gene Expression; Genes; Genetic Translation; Goals; Grant; Human; Knock-out; Lead; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Mediating; Messenger RNA; Metabolism; Molecular; Mus; Mutation; Neoplasm Metastasis; Oncogenes; Outcome; Pathologic; Pathway interactions; Patients; Phenotype; Post-Transcriptional Regulation; Proteins; Publications; RNA-Binding Proteins; Recurrent disease; Regimen; Regulation; Research; Resistance; Role; Solid Neoplasm; Specimen; Testing; Therapeutic; Tissues; Translational Regulation; Translations; Treatment Efficacy; Tumor Bank; Tumor Tissue; Xenograft Model; Xenograft procedure; base; cancer risk; cancer therapy; cancer type; chemotherapeutic agent; chemotherapy; expectation; experimental study; insight; knock-down; mRNA Stability; member; mimetics; novel; outcome forecast; overexpression; prevent; public health relevance; repaired; response; success; targeted treatment; therapy resistant; translational scientist; 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，因此突出了识别驱动侵袭性表型的新因素的需要。迄今为止，已在许多实体瘤中记录了metadherin（MTDH，也称为AEG-1和LYRIC）的过表达，并且其与不良预后相关。此外，MTDH过表达涉及转移和对治疗的抗性，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结合蛋白改变多种mRNA的翻译，从而鉴定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。本申请的目的是确定MTDH调节DNA修复在治疗抗性中的作用。该项目的基本原理是，由于MTDH在多种癌症类型中高度表达，并有助于耐药表型的出现，因此对MTDH功能的机制见解将提供一个强大的科学框架，从而可以开发MTDH途径靶向疗法。为了验证我们的中心假设，我们提出了三个具体的目标：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缺陷的癌细胞系和MTDH-/-小鼠胚胎成纤维细胞，我们将研究MTDH在mRNA代谢和Rad 18、FANCI、FANCD 2和其他DNA修复蛋白的翻译控制中的作用。我们将扩展研究，以确定是否MTDH敲低或破坏MTDH：mRNA复合物的mRNA模拟物足以扰乱MTDH的翻译调控FA途径基因。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损伤的反应来增加顺铂的治疗效果。在目标3中，我们将确定MTDH表达和FA途径活化对癌症中ICL诱导剂抗性的影响。研究将包括1）使用来自我们的存活肿瘤库的充分表征的人子宫内膜肿瘤的异种移植实验;和2）来自86名接受ICL诱导剂治疗的晚期子宫内膜癌患者的FFPE肿瘤组织中MTDH和FA途径的免疫组织化学分析。在成功完成拟议的研究后，我们期望我们将通过其对mRNA稳定性和FA途径蛋白翻译的调节来了解MTDH的病理功能。预计这些结果将产生重要的积极影响，因为它们将为MTDH过表达与治疗抗性的相关性提供强有力的机制基础，并为未来开发MTDH靶向治疗奠定基础。