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: 10240530
• 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/10240530
• 关键词: Accounting; 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 ductal adenocarcinoma cell; 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： 在美国，胰腺癌是导致癌症死亡的第四大原因。转移是主要原因 癌症死亡原因，占癌症相关死亡的高达90%。尽管……的目标 细胞毒疗法是为了最大限度地减少转移性肿瘤的生长，这种疗法专门设计来抑制 推动转移的侵袭机制目前还没有被用作胰腺癌的一部分。 治疗。我们认为，胰腺肿瘤的靶向侵袭和转移应被视为一种 治疗胰腺癌时的重要目标，即使在没有可检测到的转移疾病的情况下也是如此。这 拟议的研究计划将调查药理抗坏血酸(P-Asch-，高剂量，静脉注射)的使用 维生素C)在胰腺癌治疗中的应用。静脉注射抗坏血酸，而不是口服抗坏血酸， 产生较高的血浆浓度，对肿瘤细胞具有细胞毒性。来自我们的研究 研究小组已证实，抗坏血酸可诱导胰腺癌细胞的氧化应激和细胞毒性； 这种细胞毒性在肿瘤细胞中似乎比正常细胞更强。我们已经坚定地确定P-Asch-是一个 在肿瘤细胞中传递过氧化氢(H_2O_2)的前体药物。最近的临床研究表明 P-Asch-是安全的，耐受性很好。此外，IV期胰腺癌患者没有发生 转移性疾病，在治疗过程中转移减少，中位生存期从6 几个月到16个月。低氧诱导的上皮向间充质转化(EMT)是其中一个重要的机制。 胰腺癌转移中的事件。缺氧诱导因子-1α介导低氧反应，并在 胰腺癌。缺氧诱导因子-1α的稳定和激活触发其与肿瘤转移相关的靶基因 与许多不同的细胞过程有关，如增殖、血管生成和EMT。海流 该提案将验证过氧化氢的产生介导P-Asch诱导的转移抑制的假设 人类胰腺癌中的疾病。我们将通过以下三个具体目标来验证我们的假设：1) 确定P-Asch是否通过抑制EMT过程和肿瘤细胞侵袭而减少转移性疾病 H_2O_2介导的机制；2)确定H_2O_2代谢酶(即， 转移细胞中的过氧化氢酶)介导了对P-Asch−敏感性的增加。3)在第二阶段试验中， 确定P-Asch−联合吉西他滨/NAB-紫杉醇的疗效 无进展生存和/或总体生存。我们的建议结合了免费的方法来 证明P-Asch-可以成功地作为一种佐剂用于改善对急性髓细胞白血病的治疗 胰腺癌。此外，我们还将探讨P-Asch-1抑制肿瘤转移的机制 疾病。如果我们能严格证明P-Asch诱导的优先氧化应激和随后的 抑制胰腺癌的转移疾病，那么这项拟议的研究计划的结果将 为合理设计癌症综合治疗方案提供依据。