TDG as a novel target to enhance gemcitabine killing of pancreatic cancer cells

TDG作为增强吉西他滨杀伤胰腺癌细胞的新靶点

基本信息

批准号：
8959007
负责人：
ALFONSO BELLACOSA
金额：
$ 23.29万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8959007
关键词：
Abraxane Address Adverse effects Affect Antineoplastic Agents Base Excision Repairs Biological Products Cancer Patient Cancer cell line Cell Cycle Cell Cycle Arrest Cell Cycle Checkpoint Cell Death Cell Line Cells Cellular Stress Chromosome Segregation Clinical Trials Collection Combined Modality Therapy Coupled Cytosine DNA DNA Damage DNA Maintenance DNA Methylation DNA Repair DNA Repair Enzymes DNA Repair Inhibition DNA biosynthesis Data Deamination Defect Designer Drugs Development Disease Dose Down-Regulation Drug Formulations Drug Targeting Drug toxicity Embryo Enzymes Epidermal Growth Factor Receptor Epigenetic Process Erlotinib Exhibits FDA approved Fibroblasts Fluorouracil Future Gene Expression Genetic Genome Genome Stability Genomic Instability Genomics Germ Lines Glare Goals Growth In Vitro Individual Infection Investigation Knockout Mice Knowledge Life Expectancy Malignant Neoplasms Malignant neoplasm of pancreas Melanoma Cell Mismatch Repair Molecular Profiling Molecular Target Morphology Mus Mutation Oncogenic Paclitaxel Pathway interactions Patients Pharmaceutical Preparations Platinum Preclinical Drug Evaluation Process Proteins Radiation therapy Regimen Reporting Research Role S Phase Arrest Series Site Stress Survival Rate Testing Therapeutic Thymine DNA Glycosylase Time Toxic effect Treatment outcome Tumor-Derived Variant Xenograft procedure antiangiogenesis therapy base cancer cell cancer genome cancer therapy cell growth cell killing chemosensitizing agent chemotherapy demethylation design drug sensitivity epigenome epigenomics gemcitabine high throughput screening improved in vivo inhibitor/antagonist innovation killings melanoma methylation pattern mutant neoplastic cell novel novel strategies nucleoside analog pancreatic cancer cells personalized medicine precision medicine public health relevance receptor reconstitution repair enzyme research study response senescence small hairpin RNA small molecule treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer (PCa) is the 4th deadliest cancer in the US, with median life expectancy of less than a year. The nucleoside analog Gemcitabine (Gem) is commonly used as frontline treatment, but only extends patient survival by several months over other single agent or combination therapies. The combination of Gem + nab- paclitaxel was recently shown to extend survival by ~2 months over Gem alone. The FOLFIRINOX regimen is a formulation of multiple drugs that has shown promise by doubling (~4-6 months) survival of PCa patients over Gem alone; however, its high toxicity may limit the patients that can tolerate this regimen. Understanding and targeting the molecular mechanism responsible for chemoresistance is a rational approach to improve treatment outcomes. Inhibiting such pathways should improve drug response, and thus extend patient survival. Importantly, chemosensitizers may reduce the effective dose of chemotherapy and thus limit drug toxicity. Cancer cells rely critically on survival pathways that allow them to tolerate a broa range of extrinsic and intrinsic stresses that would normally block cell growth. Drugs such as Gem, paclitaxel, and FOLFIRINOX, inhibit DNA replication and chromosome segregation, two processes that are already destabilized in cancer cells. The survival pathways that cancer cells have evolved to tolerate genome instability are also responsible for allowing them to survive drug treatment. These pathways include those in DNA repair and cell cycle checkpoints, as they protect the cancer genome from accumulating deleterious mutations or inducing cell death. Less understood is the role of the epigenome in promoting survival of cancer cells to intrinsic and extrinsic stress; however alterations of DNA methylation patterns can have profound effects on global gene expression that may allow the tumor cell to rapidly respond to cellular stresses. We recently reported that Thymine DNA Glycosylase (TDG), a T:G mismatch repair enzyme, is also a major enzyme for active cytosine demethylation. TDG therefore is directly involved in DNA repair and maintenance of the epigenome. Indeed knockdown of TDG in tumor cells leads to S phase arrest, and accumulation of 5- carboxylcytosine (an intermediate in cytosine demethylation), and TDG-null mouse embryo fibroblasts are hypersensitive to Gem. Targeting TDG should therefore block both DNA repair and epigenome pathways that cancer cells use to survive Gem. Towards this goal, we have identified a collection of FDA-approved compounds that potently inhibit TDG in vitro. We propose in this R21 application to validate TDG as a drug target in combination with Gem, by using patient-derived PCa cells and xenografts. This is an exciting R21 proposal because of its high translational potential by dually targeting DNA repair and epigenome pathways.

描述（由应用程序提供）：胰腺癌（PCA）是美国第四个致命的癌症，预期寿命中位数不到一年。核外侧模拟吉西他滨（GEM）通常用作前线治疗，但仅将患者的存活率延长了几个月，而不是其他单一药物或联合疗法。最近显示，GEM + Nab-Nab-紫杉醇的组合可将生存延长约2个月。 FOLFIRINOX方案是多种药物的一个公式，通过将PCA患者的生存倍增（约4-6个月）与单独的GEM相比，其有望。但是，其高毒性可能会限制可以耐受该方案的患者。了解和靶向负责化学耐药的分子机制是改善治疗结果的合理方法。抑制这种途径应改善药物反应，从而延长患者的存活率。重要的是，化学剂可以减少化学疗法的有效剂量，从而限制药物毒性。癌细胞严格依靠生存途径，使它们能够忍受通常会阻止细胞生长的外部和内在应力的Broa范围。 GEM，紫杉醇和Folfirinox之类的药物抑制DNA复制和染色体分离，这两个过程已经在癌细胞中不稳定。癌细胞已经演变为耐受基因组不稳定性的生存途径也负责使其能够在药物治疗中生存。这些途径包括DNA修复和细胞周期检查点的途径，因为它们可以保护癌症基因组免受有害突变或诱发细胞死亡的影响。不太了解的是表观基因组在促进癌细胞生存到内在和外在应激的生存中的作用。但是，DNA甲基化模式的改变可能会对全球基因表达产生深远的影响，这可能使肿瘤细胞能够快速响应细胞应激。我们最近报道说，胸腺胺DNA糖基化酶（TDG）（T：G不匹配修复酶）也是活性胞嘧啶脱甲基化的主要酶。因此，TDG直接参与了表观基因组的DNA修复和维持。实际上，肿瘤细胞中TDG的敲低导致S相阻滞，并积累5-羧霉素（胞嘧啶脱甲基中的中间体），而TDG无效小鼠胚胎成纤维细胞对GEM敏感。因此，靶向TDG应阻止癌细胞用来生存GEM的DNA修复和表观基因组途径。为了实现这一目标，我们已经确定了一组FDA批准的化合物，这些化合物可能会在体外抑制TDG。我们在此R21应用中建议通过使用患者衍生的PCA细胞和异种移植物来验证TDG作为与GEM结合使用的药物靶标。这是一个令人兴奋的R21提案，因为它通过双重靶向DNA修复和表观基因组途径具有很高的翻译潜力。