Epigenetic priming in pancreatic cancer chemotherapy

胰腺癌化疗中的表观遗传启动

• 批准号: 8842837
• 负责人: RAJGOPAL GOVINDARAJAN
• 金额: $ 30.95万
• 依托单位: UNIVERSITY OF GEORGIA
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842837
• 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; 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; Xeno; Xenograft procedure; base; cancer cell; chemotherapeutic agent; chemotherapy; epithelial to mesenchymal transition; gemcitabine; histone modification; improved; in vivo; inhibitor/antagonist; innovation; nanoparticle; novel; nucleoside analog; overexpression; pancreatic cancer cells; pancreatic neoplasm; protein complex; public health relevance; 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(申请人提供)：胰腺癌是一种高度侵袭性的恶性肿瘤，对大多数化疗药物都有抗药性。核苷类似物目前被用作治疗的选择，尽管它们的益处不是最好的。我们的长期目标是改善胰腺癌的化疗管理。该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。我们推测，在胰腺癌中表观基因沉默的miR-663和-4787的修复将靶向转化生长因子-�ET-7轴，以增强核苷类似物的化疗疗效。这项研究具有重要的翻译意义，因为它将使进一步的临床研究能够提高胰腺癌患者对治疗的敏感性。引导式 通过强劲的初步数据，将通过追求三个具体目标来检验中心假设。特异性靶点1将确定miR-663和-4787在胰腺癌中的表观遗传调控。工作假说指出，由于组蛋白甲基化依赖的染色质变化，miR-663a和-4787-5p在胰腺癌中被沉默。为此，将通过a)研究miR-663和-4787启动子区域的表观遗传沉默标记，b)识别调节miR-663和-4787的表观遗传蛋白复合体，以及c)通过敲除和药理学方法评估操纵表观遗传标记和组蛋白编写者后的癌症控制结果，来研究肿瘤染色质景观。特异靶2将阐明miR-663和-4787诱导化疗增敏的机制。工作假设是miR-663和-4787的化疗增敏活性是通过转化生长因子-let-7轴减少上皮-间充质转化(EMT)驱动的耐药性而介导的。为此，我们将研究miR-663和-4787调控转化生长因子-�表达和let-7亚型成熟的详细生化机制，以了解它们在EMT导向的化疗耐药中的作用。此外，还将确定miR-663和-4787在先天和获得性核苷类似物抗性中的影响。特异性靶点3将评价miR-663和-4787对胰腺肿瘤生长的体内控制作用。工作假设是，miR-663和-4787的肿瘤递送将增强携带原位胰腺癌异种移植瘤的小鼠的吉西他滨疗效。将评估miR-663和-4787的过表达和击倒、新型核苷类似物-寡核苷酸(MiR)纳米粒制剂以及对小鼠肿瘤的流体力学传递和药代动力学。这种方法在胰腺癌化疗领域提供了实质性的创新，指导了一种新的表观遗传化疗耐药抑制剂与吉西他滨化疗药物的联合应用，以优化癌细胞的破坏。这项研究具有重要意义，因为它直接解决了胰腺癌患者核苷类似物治疗失败的压倒一切的原因-化疗耐药，并提出了一种交替的表观遗传-化疗组合方法用于临床前试验，以克服当前化疗的局限性。