Epigenetic priming in pancreatic cancer chemotherapy

胰腺癌化疗中的表观遗传启动

• 批准号: 9544025
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9544025
• 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; Duct (organ) structure; Epigenetic Process; Epithelial; Evaluation; Formulation; Funding; Goals; Growth; Histones; Human; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Mesenchymal; MicroRNAs; Modeling; Molecular; Mus; Oligonucleotides; Outcome; Pharmacology; Preclinical Testing; Promoter Regions; Public Health; Regulation; Research; Resistance; Role; Solid Neoplasm; Testing; Transforming Growth Factor alpha; Translations; Treatment Failure; Treatment Protocols; Treatment outcome; Tumor Burden; Work; Xenograft procedure; antitumor effect; 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; nanoGold; nanoparticle; novel; nucleoside analog; overexpression; pancreatic cancer cells; pancreatic neoplasm; protein complex; public health relevance; response; restoration; standard of care; targeted delivery; treatment choice; 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。尽管核苷类似物的疗效不佳，但目前仍被用作首选治疗方法。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 在胰腺癌化疗耐药中的作用。我们假设，胰腺癌中表观遗传沉默的 miR-663 和 -4787 的恢复将靶向 TGF-et-7 轴，以增强核苷类似物化疗功效。这项研究具有重要的转化意义，因为它将使得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 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 miR-663 和 -4787 在胰腺癌中的表观遗传调控。工作假设指出，由于组蛋白甲基化依赖性染色质变化，miR-663a 和 -4787-5p 在胰腺癌中被沉默。为此，我们将通过以下方式研究肿瘤染色质景观：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物，以及 c) 评估通过敲低和药理学方法操纵表观遗传标记和组蛋白书写者后的癌症控制后果。具体目标2将阐明miR-663和-4787诱导化疗增敏的机制。目前的假设是，miR-663 和 -4787 的化疗增敏活性是通过 TGF-let-7 轴减少上皮间质转化 (EMT) 驱动的耐药性来介导的。为此，将研究 miR-663 和 -4787 调节 TGF-β 表达和 let-7 亚型成熟的详细生化机制，以了解它们在 EMT 介导的化疗耐药中的作用。此外，还将确定 miR-663 和 -4787 对先天性和获得性核苷类似物耐药性的影响。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。目前的假设是，miR-663 和 -4787 的肿瘤递送将增强吉西他滨对携带原位胰腺癌异种移植物的小鼠的疗效。将评估 miR-663 和 -4787 的过表达和敲低、新型核苷类似物寡核苷酸 (miR) 纳米颗粒制剂以及向小鼠肿瘤的流体动力学递送和药代动力学。该方法通过指导共同递送新型表观遗传化疗耐药抑制剂与吉西他滨化疗药物以优化癌细胞破坏，为胰腺癌化疗领域提供了实质性创新。拟议的研究意义重大，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——化疗耐药，并提出了一种替代的表观遗传-化疗组合方法进行临床前测试，以克服当前化疗的局限性。

项目成果

ENT3 utilizes a pH Sensing Mechanism for Transport.

ENT3 利用 pH 传感机制进行运输。

• DOI: 10.1080/19336950.2017.1389581
• 发表时间: 2018
• 期刊: Channels (Austin, Tex.)
• 作者: Singh,Anusha;Govindarajan,Rajgopal
• 通讯作者: Govindarajan,Rajgopal

SET contributes to the epithelial-mesenchymal transition of pancreatic cancer.

• DOI: 10.18632/oncotarget.19067
• 发表时间: 2017-09-15
• 期刊: Oncotarget
• 作者: Mody HR;Hung SW;Naidu K;Lee H;Gilbert CA;Hoang TT;Pathak RK;Manoharan R;Muruganandan S;Govindarajan R
• 通讯作者: Govindarajan R

miR-202 Diminishes TGFβ Receptors and Attenuates TGFβ1-Induced EMT in Pancreatic Cancer.

• DOI: 10.1158/1541-7786.mcr-16-0327
• 发表时间: 2017-08
• 期刊: Molecular cancer research : MCR
• 作者: Mody HR;Hung SW;Pathak RK;Griffin J;Cruz-Monserrate Z;Govindarajan R
• 通讯作者: Govindarajan R

Bone Marrow Adipose Tissue and Skeletal Health.

• DOI: 10.1007/s11914-018-0451-y
• 发表时间: 2018-08
• 期刊: Current osteoporosis reports
• 影响因子: 4.3
• 作者: Muruganandan S;Govindarajan R;Sinal CJ
• 通讯作者: Sinal CJ

Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p.

• DOI: 10.1158/1541-7786.mcr-16-0083
• 发表时间: 2016-11
• 期刊: Molecular cancer research : MCR
• 作者: Mody HR;Hung SW;AlSaggar M;Griffin J;Govindarajan R
• 通讯作者: Govindarajan R