Pancreatic Ductal Adenocarcinoma is a disease of constitutive autophagy

摘要 胰腺导管腺癌是一种过度自噬的疾病。 摘要胰腺导管腺癌(Pda)是一种以早期全身性为特征的高度致命性疾病。 传播、生物能量学方面的干扰、炎症、凝血和对化疗的抵抗。一个 临床医生和科学家一直没有找到解释这些肿瘤相关错乱的共同联系。在……里面 人胰腺癌基因工程小鼠模型的建立 损伤相关分子模式蛋白(DAMPS)诱导的自噬是最终促进生存的关键因素 肿瘤微环境中促进癌变、肿瘤进展和抗药性的途径 心理治疗。出乎意料的是，我们现在观察到过度的自噬通量也存在于多个 小鼠模型和PDA患者的部位/器官系统。我们假设PDA是一种系统性的 湿的紊乱导致过度的自噬。成功的治疗将与恢复到 内稳态基础自噬。在这里，我们建议通过在患者身上执行一个 吉西他滨和NAB-紫杉醇联合自噬抑制剂术前应用的随机临床试验 羟基氯喹。我们最近完成了两项手术前的“原则证明”试验。 吉西他滨/羟氯喹和吉西他滨/NaB-紫杉醇；论证了其可行性、安全性和 这种方法有可能提高疗效。我们将利用临床结果和生物材料 从这三个临床试验来考察以下具体目的：具体目的一：论证 添加自噬抑制剂羟氯喹可改善术前反应 吉西他滨和那巴紫杉醇。具体目标2：证明添加了自噬抑制物 羟基氯喹将减少接受治疗的肿瘤的促生存途径。 证明PDA与潮湿诱导的过度全身自噬状态有关。

ABSTRACT Pancreatic Ductal Adenocarcinoma is a Disease of Excessive Autophagy. Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease characterized by early systemic dissemination, perturbation in bioenergetics, inflammation, coagulation, and resistance to chemotherapy. A common link to explain these tumor associated derangements has eluded clinicians and scientists. In genetically engineered murine models of human pancreatic cancer, we have demonstrated that IL-6 mediated autophagy induced by damage associated molecular pattern proteins (DAMPs) is a critical final pro-survival pathway in the tumor microenvironment promoting carcinogenesis, tumor progression and resistance to therapy. Unexpectedly we have now observed excessive autophagic flux is also present within multiple sites/organ systems in both murine models and patients with PDA. We hypothesize that PDA is a systemic disorder of DAMP induced excessive autophagy. Successful treatment will be associated with a return to homeostatic basal autophagy. Here we propose to directly address this hypothesis in patients by performing a randomized clinical trial of preoperative gemcitabine and nab-paclitaxel with or without the autophagy inhibitor hydroxychloroquine. We have recently completed two 'proof of principle' pilot trials of preoperative gemcitabine/hydroxychloroquine and gemcitabine/nab-paclitaxel; demonstrating the feasibility, safety and the potential for improved efficacy with this approach. We will utilize the clinical outcomes and biologic materials from these three clinical trials to investigate the following specific aims: Specific Aim I: Demonstrate that addition of the autophagy inhibitor hydroxychloroquine improves response to pre-operative gemcitabine and nab-paclitaxel. Specific Aim 2: Demonstrate that addition of the autophagy inhibitor hydroxychloroquine will decrease pro-survival pathways in treated tumors.Specific Aim 3: Demonstrate that PDA is associated with a state of DAMP induced excessive systemic autophagy.