Epigenetic therapy with 3-deazaneplanocin A and gemcitabine for pancreatic cancer

3-deazaneplanocin A 和吉西他滨治疗胰腺癌的表观遗传学治疗

基本信息

批准号：
8311608
负责人：
RAJGOPAL GOVINDARAJAN
金额：
$ 7.43万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8311608
关键词：
Address Amides Apoptotic Applications Grants Biochemical Bypass Cancer Patient Cancer cell line Caring Cell Culture Techniques Cells Cessation of life Characteristics Chemosensitization Combined Modality Therapy DNA DNA Methylation Data Dependence Diagnostic Neoplasm Staging Drug Kinetics Ductal Epigenetic Process Epithelial Exhibits Fatty Acids Genes Goals Growth Histones Human Hypermethylation In Vitro Intracellular Transport Investigation Laboratories Literature Malignant Neoplasms Malignant neoplasm of pancreas Methylation Molecular Biology Mus Mutation Nucleoside Transporter Nucleosides Pancreas Pharmaceutical Chemistry Pharmaceutical Preparations Pilot Projects Play Prodrugs Property Public Health Regimen Research Research Design Resistance Role Schedule Solid Neoplasm Staging Structure Testing Therapeutic Time Toxic effect Transport Process Treatment Protocols Troxacitabine Tumor Suppressor Genes Tumor stage Work Xenograft procedure base carrier mediated transport chemotherapeutic agent chemotherapy cohort comparative efficacy cytotoxic cytotoxicity demethylation gemcitabine improved in vitro testing in vivo innovation leukemia lipophilicity neoplastic cell novel nucleoside analog pancreatic cancer cells pancreatic neoplasm response

项目摘要

DESCRIPTION (provided by applicant): Despite superior cytotoxicity against early-stage pancreatic tumors, gemcitabine is practically ineffective in late-stage tumors due to the invasive growth characteristics and apoptotic resistance of tumor cells. Evidence in literature suggest that epigenetic alterations (e.g. histone and DNA hypermethylation) may play vital roles in silencing tumor suppressor genes, allowing tumor cells to clonally expand and resist cytotoxicity. Our long-term goal is to improve the chemotherapeutic management of pancreatic cancer. The overall objective of this R03 grant application is to test the concept that the reactivation of epigenetically silenced tumor suppressor genes can augment chemosensitization in pancreatic cancer. Specifically, it is our central hypothesis that a mechanism-based structure optimization of a novel histone-demethylation agent, 3'deazaneplanocin-A (DZnep), in combination with gemcitabine will enact a superior cytotoxic response in pancreatic cancer cells. This hypothesis is based on our preliminary data that show transport-dependent augmentation of gemcitabine chemosensitization by DZnep in cultured pancreatic cancer cells. The rationale underlying the proposed research is that proof of synthetic demethylating agents improving gemcitabine chemosensitivity will provide an experimental basis to continue investigating the potential of epigenetic therapy for pancreatic cancer. The central hypothesis will be tested by pursuing three specific aims. Specific aim 1 will determine the cellular transport and activation mechanisms of DZnep in pancreatic cancer. The working hypothesis for aim 1 is that the demethylating and chemosensitizing abilities of hydrophilic DZnep will be rate-limited by a carrier-mediated transport process. This hypothesis is based on our preliminary data that show a significant reduction in DZnep-induced responses when nucleoside transport activity was inhibited. Specific aim 2 will generate and test a battery of DZnep acyl derivatives in vitro. The working hypothesis for aim 2 is that N4-substituted fatty acid amide derivatives will increase the lipophilicity of DZnep and allow it to bypass the transport requirement for intracellular activation. Our hypothesis is based on our preliminary studies showing the acyl prodrugs of another nucleoside (troxacitabine) bypassing the transport requirement. Specific aim 3 will determine the in vivo anti-cancer efficacies of DZnep prodrug-gemcitabine combinations. Our working hypothesis is that the combined treatment of a DZnep prodrug with gemcitabine in mice carrying pancreatic cancer xenografts will exhibit superior chemotherapeutic efficacy compared with gemcitabine treatment alone. This hypothesis is based on the extrapolation of preliminary in vitro results obtained with DZnep and gemcitabine combination schedules in cell culture. The contribution from these studies will be significant because successful demonstration of a superior epigenetic-chemotherapeutic regimen is likely to replace the less efficacious gemcitabine monotherapy practice. The proposed work is innovative because it addresses for the first time the possibility of a nucleoside-based epigenetic-chemotherapeutic therapy in pancreatic cancer.

描述（由申请人提供）：尽管吉西他滨对早期胰腺肿瘤具有优异的细胞毒性，但由于肿瘤细胞的侵袭性生长特征和凋亡抗性，吉西他滨对晚期肿瘤实际上无效。文献证据表明，表观遗传改变（例如组蛋白和 DNA 高甲基化）可能在抑癌基因沉默中发挥重要作用，从而使肿瘤细胞能够克隆扩张并抵抗细胞毒性。我们的长期目标是改善胰腺癌的化疗管理。该 R03 拨款申请的总体目标是测试表观遗传沉默肿瘤抑制基因的重新激活可以增强胰腺癌的化疗敏感性这一概念。具体来说，我们的中心假设是，基于机制的新型组蛋白去甲基化剂 3'deazaneplanocin-A (DZnep) 与吉西他滨组合的结构优化将在胰腺癌细胞中产生优异的细胞毒性反应。这一假设基于我们的初步数据，该数据显示 DZnep 在培养的胰腺癌细胞中对吉西他滨化学增敏作用具有运输依赖性增强作用。拟议研究的基本原理是，合成去甲基化剂改善吉西他滨化学敏感性的证据将为继续研究胰腺癌表观遗传治疗的潜力提供实验基础。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 DZnep 在胰腺癌中的细胞转运和激活机制。目标 1 的工作假设是亲水性 DZnep 的去甲基化和化学增敏能力将受到载体介导的运输过程的速率限制。这一假设基于我们的初步数据，该数据显示当核苷转运活性受到抑制时，DZnep 诱导的反应显着减少。具体目标 2 将在体外生成并测试一组 DZnep 酰基衍生物。目标 2 的工作假设是 N4 取代的脂肪酸酰胺衍生物将增加 DZnep 的亲脂性，并使其绕过细胞内激活的运输要求。我们的假设基于我们的初步研究，显示另一种核苷（曲沙西他滨）的酰基前药绕过了运输要求。具体目标 3 将确定 DZnep 前药-吉西他滨组合的体内抗癌功效。我们的工作假设是，与单独使用吉西他滨治疗相比，DZnep 前药与吉西他滨联合治疗携带胰腺癌异种移植物的小鼠将表现出更优异的化疗效果。该假设基于在细胞培养中使用 DZnep 和吉西他滨组合方案获得的初步体外结果的外推。这些研究的贡献将是巨大的，因为成功证明了一种优越的表观遗传化疗方案可能会取代效果较差的吉西他滨单一疗法。这项工作具有创新性，因为它首次解决了基于核苷的表观遗传化疗治疗胰腺癌的可能性。