Epigenetic mechanisms of gemcitabine resistance in pancreatic cancer

胰腺癌吉西他滨耐药的表观遗传机制

• 批准号: 9910785
• 负责人: Chan D Nguyen
• 金额: $ 3.28万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-10 至 2022-12-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910785
• 关键词: Adenocarcinoma Cell; Affect; Affinity; Arginine; Binding; CRISPR/Cas technology; Cells; Chromatin; Combination Drug Therapy; Combined Modality Therapy; Complex; Cytostatics; DNA; DNA Methylation; Development; Disease; Disease Progression; Epigenetic Process; Genetic; Genetic Transcription; Genomic approach; Genomics; Human; Immunocompetent; In Vitro; Knock-out; Knowledge; Lead; Lysine; MLL gene; Malignant neoplasm of pancreas; Mediating; Menin; Methylation; Methyltransferase; Modeling; Mus; Neoplasms; Pancreatic Ductal Adenocarcinoma; Pharmaceutical Preparations; Phase; Phase Transition; Resistance; Resistance development; Role; Survival Rate; Tissue-Specific Gene Expression; Validation; arginine methyltransferase; base; chemotherapy; combat; epigenomics; functional genomics; gemcitabine; histone modification; in vivo; inhibitor/antagonist; insight; knock-down; mutant; novel; pancreatic cancer patients; reconstitution; response; small hairpin RNA; small molecule; transcriptome sequencing; transcriptomics; tumor

Project Summary Pancreatic ductal adenocarcinoma (PDAC) is the fourth most lethal neoplasm in the US with 5- year-survival rate of 8.5%. Currently, gemcitabine single agent or combination chemotherapies remain the most commonly used frontline treatment for locally invasive and metastatic PDAC. However, most PDAC tumors are intrinsically resistant or quickly acquire resistance to gemcitabine. Epigenetic reprogramming through changes in global DNA methylation or histone modification have been implicated in chemoresistance. Here, I established a model for gemcitabine resistance progression in PDAC and identified a cytostatic transition phase prior to regrowth under gemcitabine treatment. Through a small-molecule epigenetic inhibitor screen, I identified PRMT1 (H4R3 arginine methyltransferase) and KMT2A/B (H3K4 lysine methyltransferase) as positive and negative regulators of transition into gemcitabine resistance, respectively. Based on these findings, I hypothesize that PDAC cells transition into gemcitabine resistance through epigenetic reprogramming that is in part mediated by PRMT1 and KMT2A/B. In Aim 1, I will functionally validate PRMT1 and KMT2A/B in modulating PC gemcitabine resistance in vitro and in vivo. In Aim 2, I will investigate the mechanisms by which PRMT1 and KMT2A/B modulate gemcitabine resistance through integrated genomic analysis. Collectively, I expect my study will shed important new insight into the mechanisms of gemcitabine resistance in PDAC, which could lead to novel combination therapies to enhance the efficacies and durability of gemcitabine in PDAC.

项目摘要 胰腺导管腺癌（PDAC）是美国第四大致死性肿瘤， 年生存率8.5%。目前，吉西他滨单药或联合化疗 仍然是局部侵袭性和转移性PDAC最常用的一线治疗。 然而，大多数PDAC肿瘤是固有的耐药或快速获得耐药性， 健择。通过改变整体DNA甲基化或组蛋白的表观遗传重编程 修饰与化学抗性有关。在这里，我建立了一个模型， PDAC中的吉西他滨耐药进展，并在PDAC治疗前确定了细胞抑制过渡期。 在吉西他滨治疗下的再生长。通过小分子表观遗传抑制剂筛选， 鉴定的PRMT 1（H4 R3精氨酸甲基转移酶）和KMT 2A/B（H3 K4赖氨酸 甲基转移酶）作为转变成吉西他滨抗性的正和负调节剂， 分别基于这些发现，我假设PDAC细胞转化为吉西他滨， 通过部分由PRMT 1和KMT 2A/B介导的表观遗传重编程产生抗性。 在目标1中，我将功能性地验证PRMT 1和KMT 2A/B在调节PC吉西他滨中的作用 体外和体内的抗性。在目标2中，我将研究PRMT 1和 KMT 2A/B通过整合基因组分析调节吉西他滨耐药性。总体而言，我 我希望我的研究能为吉西他滨耐药机制提供重要的新见解 在PDAC中，这可能导致新的联合治疗，以提高疗效和持久性 吉西他滨在PDAC中的应用