Epigenetic priming in pancreatic cancer chemotherapy

胰腺癌化疗中的表观遗传启动

• 批准号: 9146298
• 负责人: RAJGOPAL GOVINDARAJAN
• 金额: $ 31.56万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9146298
• 关键词: Address; Artificial nanoparticles; Biochemical; Biodistribution; Cancer Control; Cancer Patient; Caring; Cessation of life; Chemosensitization; Chemotherapy-Oncologic Procedure; Chromatin; Clinical Research; Data; Defect; Development; Down-Regulation; Drug Kinetics; Drug resistance; Epigenetic Process; Epithelial; Evaluation; Formulation; Funding; Goals; Gold; Growth; Health; Histones; Human; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Mesenchymal; Methylation; MicroRNAs; Modeling; Molecular; Mus; Oligonucleotides; Outcome; Pancreas; Preclinical Testing; Process; Promoter Regions; Public Health; Regulation; Research; Resistance; Role; Solid Neoplasm; Testing; Translations; Treatment Failure; Treatment Protocols; Treatment outcome; Tumor Burden; Work; Xenograft procedure; base; cancer cell; chemotherapeutic agent; chemotherapy; epigenetic regulation; epithelial to mesenchymal transition; gemcitabine; histone methylation; histone modification; improved; in vivo; inhibitor/antagonist; innovation; knock-down; nanoparticle; novel; nucleoside analog; overexpression; pancreatic cancer cells; pancreatic neoplasm; protein complex; restoration; standard of care; targeted delivery; treatment choice; treatment response; tumor; tumor growth

DESCRIPTION (provided by applicant): Pancreatic cancer is a highly aggressive malignancy that is resistant to most chemotherapeutic agents. Nucleoside analogs are currently used as the treatment of choice despite their suboptimal benefits. Our long-term goal is to improve the chemotherapeutic management of pancreatic cancer. The overall objective of this application is to elucidate the role of miR-663 and -4787 in pancreatic cancer chemoresistance. We hypothesize that the restoration of miR-663 and -4787, miRs epigenetically silenced in pancreatic cancer, will target a TGF-�et-7 axis to potentiate the nucleoside analog chemotherapeutic efficacy. This research has important translational significance because it will enable further clinical studies to improve pancreatic cancer patient sensitivity to therapy. Guided by strong preliminary data, the central hypothesis will be tested by pursuing three specific aims. Specific aim 1 will determine the epigenetic regulation of miR-663 and -4787 in pancreatic cancer. The working hypothesis states that miR-663a and -4787-5p are silenced in pancreatic cancer consequent to histone methylation-dependent chromatin changes. In this aim, the tumor chromatin landscape will be investigated by a) studying the epigenetic silencing marks in the promoter regions of miR-663 and -4787, b) identifying epigenetic protein complexes regulating miR-663 and -4787, and c) evaluating the cancer control consequences after manipulation of epigenetic marks and histone writers by knockdown and pharmacological approaches. Specific aim 2 will elucidate the mechanism of miR-663 and -4787-induced chemosensitization. The working hypothesis is that the chemosensitization activities of miR-663 and -4787 are mediated by a reduction in epithelial-mesenchymal transition (EMT)-driven drug resistance via a TGF-let-7 axis. In this aim, the detailed biochemical mechanisms of miR-663 and -4787 regulation of TGF-�expression and let-7 subtypes' maturation will be investigated to understand their role in EMT-directed chemoresistance. In addition, the impact of miR-663 and -4787 in the innate and acquired nucleoside analog resistance will be determined. Specific aim 3 will evaluate the in vivo efficacy of miR-663 and -4787 in pancreatic tumor growth control. The working hypothesis is that the tumor delivery of miR-663 and -4787 will potentiate gemcitabine efficacy in mice carrying orthotopic pancreatic cancer xenografts. Overexpression and knockdown of miR-663 and -4787, novel nucleoside analog-oligonucleotide (miR) nanoparticle formulations and hydrodynamic delivery to the mouse tumors and pharmacokinetics will be evaluated. This approach offers a substantive innovation in the field of pancreatic cancer chemotherapy by directing co-delivery of a novel epigenetic chemoresistance inhibitor with the gemcitabine chemotherapeutic for optimized cancer cell destruction. The proposed research is significant because it directly addresses the overriding cause of nucleoside analog treatment failure in pancreatic cancer patients, chemoresistance, and advances an alternate epigenetic-chemotherapeutic combination approach to preclinical testing to overcome the limitations of current chemotherapy.

描述（由申请人提供）：胰腺癌是一种高度侵袭性的恶性肿瘤，对大多数化疗药物具有耐药性。核苷类似物目前被用作治疗的选择，尽管它们的效果不理想。我们的长期目标是改善胰腺癌的化疗管理。本应用的总体目标是阐明miR-663和-4787在胰腺癌化疗耐药中的作用。我们假设miR-663和-4787的恢复，miR-663和-4787在胰腺癌中被表观遗传沉默，将靶向TGF- et-7轴，以增强核苷类似物化疗疗效。本研究具有重要的翻译意义，因为它将使进一步的临床研究提高胰腺癌患者对治疗的敏感性。引导