Targeting PRMT5 to combat cancer drug resistance associated with neuroendocrine differentiation

靶向 PRMT5 对抗与神经内分泌分化相关的癌症耐药性

• 批准号: 10714956
• 负责人: Jingwei Cheng
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF NEW HAMPSHIRE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714956
• 关键词: Affect; Antineoplastic Agents; Arginine; Automobile Driving; Awareness; Benign; Biological Assay; Biology; Biomedical Engineering; Carcinoma; Cell Line; Cell secretion; ChIP-seq; Clinical; Clinical Trials; Colorectal Cancer; Data; Drug resistance; Epigenetic Process; Epithelium; Exhibits; Gastrointestinal Neoplasms; Gastrointestinal Neuroendocrine Neoplasm; Gene Expression; Genomics; Goals; Growth; Histones; Incidence; Lead; Link; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Merkel Cells; Merkel cell carcinoma; Methylation; Modeling; Modification; Molecular; Mutation; N,N-dimethylarginine; Neoplasm Metastasis; Neoplasms; Neuroendocrine Cell; Neuroendocrine Therapy; Neuroendocrine Tumors; Neurosecretory Systems; Oncogenic; Organ; Pathologic; Patients; Pattern; Phenotype; Polyomavirus; Prevalence; Protein-Arginine N-Methyltransferase; RNA analysis; Radiation; Research; Resistance; Role; Site; Skin; Survival Rate; Testing; Therapeutic Intervention; United States; Variant; Viral; Viral Antigens; Virus; c-myc Genes; cancer clinical trial; cancer drug resistance; cancer therapy; cancer type; carcinogenesis; cell growth; combat; conventional therapy; dimethylarginine; drug sensitivity; histone methylation; inhibitor; insight; malignant breast neoplasm; malignant stomach neoplasm; melanoma; neoplastic cell; neuroendocrine differentiation; paralogous gene; peptide hormone; protein arginine methyltransferase 2; protein complex; protein degradation; response; small cell lung carcinoma; small hairpin RNA; stemness; targeted treatment; therapy development; transcription factor; transcriptome sequencing; transdifferentiation; tumorigenesis

PROJECT SUMMARY Neuroendocrine Tumors (NETs) occur in multiple organs and share many similarities. Although NETs are relatively rare compared to breast and lung cancers, the incidence of NETs is steadily increasing. Conventional therapies are not effective in treating NETs, and the survival rates of patients with NETs remain low. Trans- differentiation to NETs is suggested as a mechanism of cancer therapy resistance across all epithelial cancers, therefore it is important to understand the initiation and progression of NETs. However, challenges in studying NETs have limited progress in developing therapies. Merkel cell carcinoma (MCC) is a high-grade NET of the skin that is more deadly than melanoma, with about 80% of cases caused by Merkel cell polyomavirus. This type of NET with its viral oncogenic causal factors is thus a valuable model to investigate the biology of NETs. NETs normally exhibit low mutation rates, and epigenetic modifications are hypothesized to be important drivers. In this proposal, we will critically evaluate the role of Protein Arginine Methyltransferase 5 (PRMT5) in MCC as an epigenetic regulator in MCC by investigating PRMT5-mediated arginine methylation that is associated with neuroendocrine differentiation. We hypothesize that PRMT5-mediated histone methylation and downstream targets affected by this methylation are required for the maintenance of NET state of MCC and can additionally affect cancer drug resistance. This project will (1) determine effects of PRMT5 on the NET identity of MCC and drug resistance, and (2) identify PRMT5 targets associated with the NET state of MCC. Inhibitors for PRMT5 are currently in clinical trials for several types of cancer, and understanding the molecular mechanisms of PRMT5 as an epigenetic regulator in MCC will help evaluate the use of PRMT5 inhibitors as a potential therapeutic intervention not only for MCC but also for the treatment of other NETs.

项目概要 神经内分泌肿瘤 (NET) 发生在多个器官中，并且有许多相似之处。尽管 NET 是 与乳腺癌和肺癌相比，NET 的发病率相对较少，但其发病率正在稳步上升。传统的 治疗方法对治疗 NET 无效，并且 NET 患者的生存率仍然很低。反式 NETs 的分化被认为是所有上皮癌的癌症治疗耐药性机制， 因此，了解 NET 的起源和发展非常重要。然而学习中的挑战 NET 在开发疗法方面进展有限。默克尔细胞癌 (MCC) 是一种高级别 NET 比黑色素瘤更致命的皮肤病，大约 80% 的病例是由默克尔细胞多瘤病毒引起的。这种类型 因此，NET 及其病毒致癌因素是研究 NET 生物学的一个有价值的模型。网络 通常表现出较低的突变率，并且表观遗传修饰被认为是重要的驱动因素。在 在此提案中，我们将严格评估蛋白精氨酸甲基转移酶 5 (PRMT5) 作为 MCC 的作用 通过研究与相关的 PRMT5 介导的精氨酸甲基化，研究 MCC 中的表观遗传调节因子 神经内分泌分化。我们假设 PRMT5 介导的组蛋白甲基化及其下游 受这种甲基化影响的目标是维持 MCC 的 NET 状态所必需的，并且还可以 影响癌症耐药性。该项目将 (1) 确定 PRMT5 对 MCC 的 NET 身份的影响，以及 耐药性，(2) 确定与 MCC NET 状态相关的 PRMT5 靶点。 PRMT5 抑制剂是 目前正在进行多种癌症的临床试验，并了解PRMT5的分子机制 作为 MCC 的表观遗传调节剂将有助于评估 PRMT5 抑制剂作为潜在治疗方法的用途 干预不仅针对 MCC，还针对其他 NET 的治疗。