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

项目概要/摘要-项目1： 胰腺腺癌是美国癌症死亡的第四大原因。 癌症是导致死亡的主要原因，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限度地减少转移性肿瘤生长，专门设计用于抑制肿瘤生长的疗法。 驱动转移的侵袭机制目前未被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认为是一种治疗胰腺癌的有效方法。 这是治疗胰腺癌时的重要目标，即使在没有可检测到的转移性疾病的情况下。这 一项拟议的研究计划将调查使用药理学抗坏血酸（P-AscH-，高剂量，静脉注射 维生素C的递送）在胰腺癌的治疗中。静脉注射抗坏血酸，而不是口服抗坏血酸， 产生高血浆浓度，其在对肿瘤细胞具有细胞毒性的范围内。我们的研究 研究小组已经证明，抗坏血酸诱导胰腺癌细胞的氧化应激和细胞毒性; 这种细胞毒性似乎在肿瘤细胞中比在正常细胞中更大。我们已经确定P-AscH-是一个 用于在肿瘤细胞中递送过氧化氢（H2 O2）的前药。近期临床研究已经证实 P-AscH是安全的并且耐受性良好此外，IV期胰腺癌患者未发生 转移性疾病，治疗期间转移减少，中位生存期从6 个月至16个月。缺氧诱导的上皮细胞向间充质细胞转化（EMT）是细胞增殖的关键因素之一， 胰腺癌转移中的事件。HIF-1α介导缺氧反应，并在细胞中过表达。 胰腺癌HIF-1α的稳定和激活触发其与转移相关的靶基因， 与许多不同的细胞过程相关，如增殖、血管生成和EMT。当前 一项提案将检验H2 O2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检验我们的假设：1） 确定P-AscH是否通过抑制EMT过程和肿瘤细胞侵袭来减少转移性疾病， H2 O2-介导的机制; 2）确定是否降低H2 O2-代谢酶的表达（即， 过氧化氢酶）介导对P-AscH−的敏感性增加。3)在第二阶段试验中， 确定P-AscH−联合吉西他滨/nab-Paclitaxel的疗效，定义为 无进展生存期和/或总生存期。我们的建议结合了互补的方法， 证明P-AscH-可以成功地用作佐剂，以改善治疗中的反应， 胰腺癌此外，我们将研究P-AscH-抑制转移的机制， 疾病如果我们能严格证明P-AscH诱导优先氧化应激， 抑制胰腺癌的转移性疾病，那么这项研究计划的结果将 为合理设计癌症综合治疗方案提供依据。

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.