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Characterization of Drug Survival by Pancreatic Cancer Cells in vitro and in vivo

胰腺癌细胞体外和体内药物存活的表征

基本信息

批准号：
8883439
负责人：
Timothy Yen
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：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8883439
关键词：
Address Adverse effects Affect Alleles Androgen Antagonists Antifungal Agents Antimitotic Agents Biological Biological Products Calcium Cancer Patient Cell Cycle Checkpoint Cell Survival Cells Chemosensitization Cholecalciferol Chromosome Segregation Combined Modality Therapy DNA Damage DNA Repair DNA biosynthesis DNA damage checkpoint Data Diagnosis Disease Dose Drug Formulations Early Diagnosis Enzyme Precursors Epidermal Growth Factor Receptor Erlotinib Fluorouracil Genes Genetic Transcription Genomic Instability Health Homeostasis In Vitro Indium Individual Ketoconazole Lead Leucovorin Libraries Life Expectancy Ligands Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Mediating Metabolism Molecular Molecular Target Paclitaxel Pancreas Pathway interactions Patients Pharmaceutical Preparations Physiologic calcification Platinum Process Production RNA Interference Radiation therapy Regimen Research Resistance Role Skin Small Interfering RNA Staging Stress Survival Rate Testing Time Toxic effect Transactivation Treatment outcome Vitamin D Vitamin D3 Receptor Xenograft Model Xenograft procedure base cancer cell cell growth chemosensitizing agent chemotherapeutic agent chemotherapy efficacy testing gemcitabine genome-wide improved in vivo inhibitor/antagonist innovation insight irinotecan killings mouse model mutant neoplastic cell novel nucleoside analog oxaliplatin pancreatic cancer cells phase III trial programs promoter receptor expression response transcription factor transcriptome sequencing treatment strategy tumor tumor growth tumor xenograft

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. PCa does not respond well to conventional chemotherapies as the disease has progressed to late stages by the time of diagnosis. 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 pancreatic cancer patients over gemcitabine alone. However, high toxicity associated with this treatment may limit the patients that can tolerate this regimen. Understanding and targeting the molecular mechanism responsible for chemoresistance is a rational approach to improving treatment outcomes. Inhibiting such pathways should allow existing drugs to kill more tumor cells, and thus extend patient survival. Importantly, chemosensitizers may reduce the effective dose of chemo and thus also reduce toxic side effects. Cancer cells rely critically on survival pathways that allow them to tolerate a broad range of extrinsic and intrinsic stresses that would normally block cell growth. Drugs such as gemcitabine, paclitaxel, and FOLFIRINOX inhibit DNA replication and chromosome segregation, two processes that are already destabilized in cancer cells. The survival pathways that have evolved to allow cancer cells to tolerate genome instability are likely responsible for allowing cells to survive treatment with these drugs. We conducted a genome-wide siRNA screen to identify genes that are critically important for the survival of pancreatic cancer cells treated with gemcitabine. This effort revealed an unexpected role for the Vitamin D receptor (VDR) transcription factor in dictating cell survival in response to drugs. VDR is activated by 1,25-OH vitamin D3 and is best known for regulating genes important for calcium homeostasis and bone mineralization. We have identified a new role in promoting DNA repair that is crucial for gemcitabine survival by pancreatic cancer cells. Our combined molecular, pharmacological and cell biological data strongly suggest that VDR is essential for pancreatic cancer cells to survive gemcitabine treatment. We believe that this reflects evolutionary adaptation of the importance of VDR in protecting skin from the harmful yet necessary benefits of UV in the production of Vitamin D. We propose in this R21 application to address how VDR is used by pancreatic cancer cells to survive gemcitabine and other chemotherapeutic agents. We will also conduct in vivo studies that test the efficacy of an anti-fungal drug in enhancing Gem killing of a PCa patient derived tumor xenograft, as well as a mouse model for the disease. This is an exciting R21 proposal because of its high translational potential and novel insights into how PCa cells survive drug treatment.

描述（由申请人提供）：胰腺癌 (PCa) 是美国第四大致命癌症，中位预期寿命不到一年。 PCa 对传统化疗的反应不佳，因为在诊断时该疾病已发展至晚期。吉西他滨 (Gem) 通常用作一线治疗，但与其他单药或联合疗法相比只能将患者的生存期延长几个月。最近显示，Gem + 白蛋白结合型紫杉醇的组合比单独使用 Gem 可以延长约 2 个月的生存期。 FOLFIRINOX 方案是多种药物的配方，与单独使用吉西他滨相比，该方案有望使胰腺癌患者的生存期延长一倍（约 4-6 个月）。然而，与该治疗相关的高毒性可能会限制能够耐受该方案的患者。了解和靶向导致化疗耐药的分子机制是改善治疗结果的合理方法。抑制这些途径应该能让现有药物杀死更多的肿瘤细胞，从而延长患者的生存期。重要的是，化疗增敏剂可以减少化疗的有效剂量，从而减少毒副作用。癌细胞严重依赖生存途径，使它们能够耐受通常会阻碍细胞生长的广泛的外在和内在压力。吉西他滨、紫杉醇和 FOLFIRINOX 等药物会抑制 DNA 复制和染色体分离，这两个过程在癌细胞中已经不稳定。已经进化到允许癌细胞耐受基因组不稳定性的生存途径可能是允许细胞在这些药物治疗后存活下来的原因。我们进行了全基因组 siRNA 筛选，以确定对吉西他滨治疗的胰腺癌细胞的存活至关重要的基因。这项工作揭示了维生素 D 受体 (VDR) 转录因子在决定细胞对药物反应的存活方面发挥着意想不到的作用。 VDR 由 1,25-OH 维生素 D3 激活，以调节对钙稳态和骨矿化重要的基因而闻名。我们已经确定了促进 DNA 修复的新作用，这对于吉西他滨胰腺癌细胞的存活至关重要。我们综合的分子、药理学和细胞生物学数据强烈表明，VDR 对于胰腺癌细胞在吉西他滨治疗中存活至关重要。我们认为，这反映了 VDR 在保护皮肤免受维生素 D 生产过程中紫外线有害但必要的益处方面的重要性的进化适应。我们在此 R21 申请中建议解决胰腺癌细胞如何利用 VDR 来生存吉西他滨和其他化疗药物。我们还将进行体内研究，测试抗真菌药物在增强 Gem 杀死细菌方面的功效。 PCa 患者衍生的肿瘤异种移植物，以及该疾病的小鼠模型。这是一个令人兴奋的 R21 提案，因为它具有很高的转化潜力以及对 PCa 细胞如何在药物治疗中存活的新颖见解。