Pancreatic Ductal Adenocarcinoma is a disease of constitutive autophagy

描述（申请人提供）：胰腺导管腺癌是一种过度自噬的疾病。胰腺导管腺癌（PDA）是一种高致死率的疾病，其特点是早期全身播散、生物能量紊乱、炎症、凝血和化疗耐药。临床医生和科学家们一直没有找到解释这些肿瘤相关紊乱的共同联系。在人类胰腺癌的基因工程小鼠模型中，我们已经证明损伤相关分子模式蛋白（DAMPs）诱导的IL-6介导的自噬是肿瘤微环境中促进癌变、肿瘤进展和治疗抵抗的关键最终促生存途径。出乎意料的是，我们现在在小鼠模型和PDA患者的多个部位/器官系统中也观察到过度的自噬通量。我们假设PDA是一种由DAMP引起的过度自噬的全身性疾病。成功的治疗将与恢复稳态基础自噬有关。在这里，我们建议在患者中直接解决这一假设，通过进行术前吉西他滨和nab-紫杉醇加或不加自噬抑制剂羟氯喹的随机临床试验。我们最近完成了术前吉西他滨/羟氯喹和吉西他滨/nab-紫杉醇的两项“原理证明”试点试验；证明这种方法的可行性、安全性和提高疗效的潜力。我们将利用这三个临床试验的临床结果和生物材料来探讨以下具体目标：具体目标1：证明自噬抑制剂羟氯喹的加入可以改善术前吉西他滨和nab-紫杉醇的反应。特异性目的2：证明添加自噬抑制剂羟氯喹将减少治疗肿瘤的促生存途径。具体目标3：证明PDA与DAMP诱导的过度全身自噬状态有关。

DESCRIPTION (provided by applicant): 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.