Project 1: Inhibition of Metastasis Utilizing Pharmacological Ascorbate in Pancreas Cancer

项目1：利用药理抗坏血酸抑制胰腺癌转移

• 批准号: 10005900
• 负责人: Joseph J Cullen
• 金额: $ 50.91万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005900
• 关键词: Accounting; Adenocarcinoma Cell; Adjuvant; Ascorbic Acid; Cancer Etiology; Cell Respiration; Cell physiology; Cells; Cessation of life; Chemotherapy and/or radiation; Clinical; Clinical Data; Clinical Research; Clinical Trials; Cytotoxic Chemotherapy; Data; Development; Disease; Distant; Dose; Enzymes; Event; Foundations; Generations; Genes; Glioblastoma; Goals; Human; Hydrogen Peroxide; Hypoxia; Image; In Vitro; Intravenous; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolism; Metastatic Neoplasm to the Liver; Modality; Neoplasm Metastasis; Normal Cell; Outcome; Oxidation-Reduction; Oxidative Stress; Paclitaxel; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmacologic Ascorbate; Plasma; Process; Prodrugs; Production; Progression-Free Survivals; Research; Testing; Tumor Cell Invasion; angiogenesis; ascorbate; base; cancer cell; cancer therapy; catalase; chemotherapy; combined cancer modality therapy; cytotoxic; cytotoxicity; design; epithelial to mesenchymal transition; gemcitabine; improved; in vivo; iron metabolism; metastatic process; mortality; neoplastic cell; novel; overexpression; oxidation; pancreatic cancer cells; pancreatic neoplasm; phase II trial; phase III trial; pre-clinical; predictive marker; programs; response; success; therapy outcome; tumor; tumor growth

Project Summary/Abstract - Project 1: Adenocarcinoma of the pancreas is the 4th leading cause of cancer death in the U.S. Metastasis is a major cause of cancer mortality, accounting for as many as 90% of cancer-related deaths. Although a goal of cytotoxic therapies is to minimize metastatic tumor growth, therapies specifically designed to inhibit the mechanisms of invasion that drive metastasis are not currently utilized as a part of pancreatic cancer treatment. We believe that targeting invasion and metastasis of pancreatic tumors should be considered as an important goal when treating pancreatic cancer, even in the absence of detectable metastatic disease. This proposed research program will investigate the use of pharmacologic ascorbate (P-AscH-, high-dose, IV delivery of vitamin C) in the treatment of pancreatic cancer. Intravenous ascorbate, but not oral ascorbate, produces high plasma concentrations, which are in the range that are cytotoxic to tumor cells. Studies from our group have demonstrated that ascorbate induces oxidative stress and cytotoxicity in pancreatic cancer cells; this cytotoxicity appears to be greater in tumor vs. normal cells. We have firmly established that P-AscH- is a pro-drug for delivery of hydrogen peroxide (H2O2) in tumor cells. Recent clinical studies have demonstrated that P-AscH- is safe and well tolerated. In addition, patients with stage IV pancreatic cancer did not develop metastatic disease, had reductions in metastases during treatment, and increased median survival from 6 months to 16 months. Epithelial-to-mesenchymal transition (EMT) induced by hypoxia is one of the critical events in pancreatic cancer metastases. HIF-1α mediates hypoxia responses and is overexpressed in pancreatic cancer. Stabilization and activation of HIF-1α triggers its target genes related to metastasis, which correlate with many difference cellular processes, such as proliferation, angiogenesis and EMT. The current proposal will test the hypothesis that production of H2O2 mediates P-AscH--induced inhibition of metastatic disease in human pancreatic cancer. We will test our hypothesis with the following three Specific Aims: 1) Determine if P-AscH- reduces metastatic disease by inhibiting the EMT process and tumor cell invasion via a H2O2-mediated mechanism; 2) Determine if decreased expression of H2O2-metabolizing enzymes (i.e., catalase) in metastatic PDAC cells mediates the increased sensitivity to P-AscH−. 3) In a phase II trial, determine efficacy of P-AscH− combined with gemcitabine/nab-Paclitaxel as defined by an increase in progression free survival and/or overall survival. Our proposal combines complimentary approaches to demonstrate that P-AscH- can be used successfully as an adjuvant to improve responses in the treatment of pancreatic cancer. Furthermore, we will investigate the mechanism by which P-AscH- inhibits metastatic disease. If we can rigorously demonstrate that P-AscH- induces preferential oxidative stress and subsequent inhibition of metastatic disease in pancreatic cancer, then the results of this proposed research program will provide a foundation for the rational design of a combined modality cancer therapy.

项目摘要/摘要 - 项目1： 胰腺腺癌是美国转移癌症死亡的第四个主要原因是主要的 癌症死亡率的原因，占癌症相关死亡的90％。虽然目标是 细胞毒性疗法是为了最大程度地减少转移性肿瘤的生长，专门设计用于抑制的疗法 目前尚未将驱动转移的入侵机制用作胰腺癌的一部分 治疗。我们认为，靶向胰腺肿瘤的侵袭和转移应被视为 即使没有可检测的转移性疾病，也可以治疗胰腺癌时的重要目标。这 拟议的研究计划将调查使用药物抗坏血酸（P-ASCH-，高剂量，IV）的使用 维生素c）在治疗胰腺癌方面。静脉注射抗坏血酸，但不是口服抗坏血酸盐， 产生高血浆浓度，该血浆浓度在肿瘤细胞的细胞毒性范围内。我们的研究 组表明，抗坏血酸诱导胰腺癌细胞中的氧化应激和细胞毒性。 在肿瘤与正常细胞中，这种细胞毒性似乎更大。我们首先确定p-asch-是 促药在肿瘤细胞中递送过氧化氢（H2O2）。最近的临床研究表明 该P-Asch-安全且容忍良好。此外，IV期胰腺癌患者没有发展 转移性疾病，治疗过程中转移量减少，中位存活率从6个增加 月至16个月。缺氧诱导的上皮到间质转变（EMT）是关键之一 胰腺癌转移的事件。 HIF-1α介导缺氧反应，并在 胰腺癌。 HIF-1α的稳定和激活触发与转移有关的靶基因 与许多差异相关的细胞过程，例如增殖，血管生成和EMT。电流 提案将检验以下假设：H2O2的产生介导P-ASCH诱导的转移性抑制 人类胰腺癌的疾病。我们将通过以下三个特定目的测试我们的假设：1） 确定P-ASCH-是否通过通过A抑制EMT过程和肿瘤细胞侵袭来降低转移性疾病 H2O2介导的机制； 2）确定H2O2-替代酶的表达降低（即 转移性PDAC细胞中的过氧化氢酶）介导对P-ASCH-的敏感性增加。 3）在II期试验中， 确定P-ASCH-与吉西他滨/NAB-甲酰胺的效率，这是由增加的效率 无进展生存和/或总体生存。我们的提议结合了免费的方法 证明p-asch-可以成功地用作调整以改善治疗的反应 胰腺癌。此外，我们将研究P-Asch抑制转移性的机制 疾病。如果我们能严格证明p-asch-诱导优先氧化应力，然后 抑制胰腺癌转移性疾病的抑制作用，那么该提出的研究计划的结果将 为合并方式癌症治疗的合理设计提供了基础。