Epigenetic priming in pancreatic cancer chemotherapy

胰腺癌化疗中的表观遗传启动

• 批准号: 8928102
• 负责人: RAJGOPAL GOVINDARAJAN
• 金额: $ 31.96万
• 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/8928102
• 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 Formulations; Drug Kinetics; Drug resistance; Epigenetic Process; Epithelial; Evaluation; 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; Therapeutic; 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; nanoparticle; novel; nucleoside analog; overexpression; pancreatic cancer cells; pancreatic neoplasm; protein complex; response; restoration; standard of care; targeted delivery; 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，尽管它们的次优效益。我们的长期目标是改善胰腺癌的化疗管理。本申请的总体目标是阐明miR-663和-4787在胰腺癌化学抗性中的作用。我们假设，miR-663和-4787（胰腺癌中表观遗传学沉默的miR）的恢复将靶向TGF-β et-7轴，以增强核苷类似物化疗的疗效。这项研究具有重要的转化意义，因为它将使进一步的临床研究，以提高胰腺癌患者对治疗的敏感性。指导 通过强有力的初步数据，将通过追求三个具体目标来检验中心假设。具体目标1将确定胰腺癌中miR-663和-4787的表观遗传调控。工作假设表明，miR-663 a和-4787-5p在胰腺癌中沉默，导致组蛋白甲基化依赖性染色质变化。为此，将通过a）研究miR-663和-4787的启动子区域中的表观遗传沉默标记，B）鉴定调节miR-663和-4787的表观遗传蛋白复合物，和c）通过敲低和药理学方法评估操作表观遗传标记和组蛋白编写器后的癌症控制结果，来研究肿瘤染色质景观。具体目标2将阐明miR-663和-4787诱导的化学增敏的机制。工作假设是miR-663和-4787的化学增敏活性通过减少上皮-间充质转化（EMT）驱动的耐药性经由TGF-let-7轴介导。在这个目标中，miR-663和-4787调节TGF-β表达和let-7亚型成熟的详细生化机制将被研究，以了解它们在EMT介导的化疗耐药性中的作用。此外，将确定miR-663和-4787在先天性和获得性核苷类似物耐药性中的影响。具体目标3将评估miR-663和-4787在胰腺肿瘤生长控制中的体内功效。工作假设是miR-663和-4787的肿瘤递送将增强吉西他滨在携带原位胰腺癌异种移植物的小鼠中的功效。将评价miR-663和-4787的过表达和敲低、新型核苷类似物-寡核苷酸（miR）纳米颗粒制剂和向小鼠肿瘤的流体动力学递送以及药代动力学。该方法通过指导新型表观遗传化学抗性抑制剂与吉西他滨化疗剂的共递送以优化癌细胞破坏，在胰腺癌化疗领域提供了实质性创新。这项研究意义重大，因为它直接解决了胰腺癌患者核苷类似物治疗失败的首要原因，即化疗耐药性，并将替代表观遗传-化疗联合方法推向临床前测试，以克服目前化疗的局限性。