The Role of MK2 pathway on head and neck cancer epithelial-to-mesenchymal transiston and tumor metastasis

MK2通路在头颈癌上皮间质转移及肿瘤转移中的作用

• 批准号: 10115130
• 负责人: Gregory N Gan
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115130
• 关键词: Address; Affect; Automobile Driving; Biological; Biological Assay; Biological Markers; Biology; Biomedical Engineering; CRISPR/Cas technology; Cancer Etiology; Cancer Patient; Carcinoma; Cell Line; Cells; Cessation of life; Clinical; DNA; DNA Methylation; Development; Distant; Distant Metastasis; Epithelial; Foundations; Future; Gene Expression; Gene Silencing; Generations; Genes; Goals; HSPB1 gene; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Hypermethylation; In Vitro; Inflammatory; Institutes; Intervention; Kansas; Knock-in; Knock-out; Knowledge; Larynx; Link; Lung Neoplasms; MAP Kinase Gene; MAPKAPK2 gene; Malignant neoplasm of lung; Mediating; Mesenchymal; Metastatic Neoplasm to the Lung; Methylation; Modeling; Molecular; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Oncogenes; Oral cavity; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphorylation; Precision medicine trial; Preclinical Testing; Process; Production; Prognostic Factor; Prognostic Marker; Proteins; Radiation; Radiation Tolerance; Radiation therapy; Recurrence; Research; Role; Signal Pathway; Testing; Tissue Microarray; Tumor Cell Invasion; Tumor Cell Line; United States National Institutes of Health; Up-Regulation; Work; biobank; biomarker validation; cytokine; design; druggable target; epithelial to mesenchymal transition; first-in-human; improved; in vivo; inhibitor/antagonist; methylation pattern; methylome; mouse model; novel; novel therapeutics; p38 Mitogen Activated Protein Kinase; patient stratification; phase 1 testing; pre-clinical; precision medicine; promoter; targeted treatment; therapy resistant; transcriptomics; treatment strategy; tumor; tumor growth; tumorigenesis

Tumor metastasis remains a devastating problem for all cancer patients and is the major cause of cancer related death in head and neck squamous cell carcinoma (HNSCC) patients in the US. An important biologic and clinical question is how tumor metastasis and treatment resistance are regulated. One mechanism that can regulate both these processes is epithelial-to-mesenchymal transition (EMT). We have identified the MAPKAPK2 (MK2) pathway as a potential regulator of radiation-mediated tumor EMT. However, it remains unknown what effect MK2 activation has on epithelial gene silencing through DNA methylation; whether MK2 pathway is important for generation of circulating tumor cells (CTCs); and whether MK2 can be used as a biomarker to prognosticate HNSCC patient metastasis-free survival. The objective of this current proposal is to determine if HNSCC EMT can regulate tumor metastasis via MK2 pathway activation. We hypothesize that MK2 activation can increase HNSCC metastasis through epithelial gene silencing, upregulation of CTCs via EMT and serve as a prognostic marker for metastatic or recurrent HNSCC. Our proposed work is focused on two specific goals. First, increase our knowledge of MK2 biology using MK2 wildtype and knockout cell lines (in the presence or absence of radiotherapy) and how it can directly affect the DNA methylome through epithelial gene silencing and EMT gene expression; how MK2 activation can regulate tumor growth, EMT and the production of circulating tumor cells (CTCs); and whether high MK2 phosphorylation levels can prognosticate HNSCC patient loco-regional and distant metastasis-free survival. Second, we have access to a Phase I tested MK2 inhibitor which we will begin preclinical testing of this compound with radiotherapy. The significance of studying MK2 biology will provide a better in vivo biological mechanism linking how tumor EMT can regulate treatment resistance and facilitate metastasis. The overall clinical impact of this work will allow us to develop better treatment strategies aimed at improving tumor control and long-term patient survival. My long-term research goal is to identify the molecular determinants involved in HNSCC metastasis and to identify druggable targets to address this significant problem. This preclinical work will lay the foundation for a future precision medicine trial aimed at stratifying patients who express high MK2 phosphorylation for active intervention with a MK2 inhibitor and radiotherapy.

肿瘤转移仍然是所有癌症患者的毁灭性问题，并且是美国头颈部鳞状细胞癌（HNSCC）患者中癌症相关死亡的主要原因。一个重要的生物学和临床问题是如何调节肿瘤转移和治疗抗性。可以调节这两个过程的一种机制是上皮-间充质转化（EMT）。我们已经确定了MAPKAPK 2（MK2）途径作为辐射介导的肿瘤EMT的潜在调节因子。然而，目前尚不清楚MK2激活对通过DNA甲基化的上皮基因沉默的影响; MK2途径是否对循环肿瘤细胞（CTC）的产生很重要;以及MK2是否可以用作生物标志物来预测HNSCC患者的无转移生存期。本提案的目的是确定HNSCC EMT是否可以通过MK2途径激活来调节肿瘤转移。我们假设MK2激活可以通过上皮基因沉默增加HNSCC转移，通过EMT上调CTC，并作为转移性或复发性HNSCC的预后标志物。我们建议的工作侧重于两个具体目标。首先，使用MK2野生型和敲除细胞系增加我们对MK2生物学的了解（在存在或不存在放射治疗的情况下）以及它如何通过上皮基因沉默和EMT基因表达直接影响DNA甲基化组; MK2活化如何调节肿瘤生长、EMT和循环肿瘤细胞（CTC）的产生;以及高MK2磷酸化水平是否可以预测HNSCC患者局部区域和远端无转移生存率。第二，我们获得了一种经过I期测试的MK 2抑制剂，我们将开始用放射疗法对这种化合物进行临床前测试。研究MK2生物学的意义将提供更好的体内生物学机制，将肿瘤EMT如何调节治疗抗性和促进转移联系起来。这项工作的整体临床影响将使我们能够开发更好的治疗策略，旨在改善肿瘤控制和长期患者生存。我的长期研究目标是确定参与HNSCC转移的分子决定因素，并确定可药物靶点以解决这一重大问题。这项临床前工作将为未来的精准医学试验奠定基础，该试验旨在对表达高MK2磷酸化的患者进行分层，以便使用MK2抑制剂和放疗进行积极干预。