Pancreatic Ductal Adenocarcinoma is a disease of constitutive autophagy

胰腺导管腺癌是一种组成性自噬疾病

• 批准号: 8612934
• 负责人: MICHAEL T LOTZE
• 金额: $ 31.58万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8612934
• 关键词: Address; Adjuvant; Apoptosis; Apoptotic; Autophagocytosis; Bioenergetics; Biological Assay; Cancer Etiology; Cell Death; Cell Survival; Cessation of life; Clinical; Clinical Trials; Coagulation Process; Cytotoxic Chemotherapy; Data; Disease; Excision; Future; Genetic Engineering; HMGB1 gene; Histologic; Human; Hydroxychloroquine; Incidence; Inflammation; Interleukin-6; Link; Liver; Malignant neoplasm of pancreas; Measures; Mediating; Mediator of activation protein; Metric; Modeling; Molecular; Mus; Operative Surgical Procedures; Organ; Outcome; Paclitaxel; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Participant; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phase; Positron-Emission Tomography; Proteins; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Resistance; STAT3 gene; Safety; Scientist; Serum Markers; Signal Pathway; Signal Transduction; Site; Testing; Therapeutic Intervention; United States; University of Pittsburgh Cancer Institute; base; body system; carcinogenesis; chemotherapy; clinical efficacy; gemcitabine; improved; inhibition of autophagy; inhibitor/antagonist; mortality; neoplastic cell; novel; pancreatic neoplasm; peripheral blood; pilot trial; pre-clinical; preclinical study; public health relevance; randomized trial; response; therapy resistant; tumor; tumor microenvironment; tumor progression

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.

摘要 胰腺导管腺癌是一种过度自噬性疾病。 胰腺导管腺癌（PDA）是一种高致死性疾病，其特征在于早期全身性 传播、生物能量学干扰、炎症、凝血和对化疗的抗性。一 临床医生和科学家们一直没有找到一个共同的联系来解释这些肿瘤相关的紊乱。在 在人胰腺癌的基因工程小鼠模型中，我们已经证明了IL-6介导的 损伤相关分子模式蛋白（DAMPs）诱导的自噬是一种关键的终末促生存因子， 在肿瘤微环境中促进癌发生、肿瘤进展和对 疗法出乎意料的是，我们现在已经观察到过度的自噬通量也存在于多个细胞中。 在小鼠模型和PDA患者中的部位/器官系统。我们假设PDA是一种系统性的 DAMP的紊乱诱导了过度的自噬。成功的治疗将与恢复 稳态基础自噬。在这里，我们建议直接解决这一假设的患者，通过执行一个 术前吉西他滨和白蛋白结合型紫杉醇联合或不联合自噬抑制剂的随机临床试验 羟氯喹我们最近完成了两个“原则证明”的试点试验， 吉西他滨/羟氯喹和吉西他滨/nab-紫杉醇;证明了可行性、安全性和 这种方法提高疗效的潜力。我们将利用临床结果和生物材料 从这三个临床试验中研究以下具体目标：具体目标I：证明 自噬抑制剂羟氯喹的加入改善了对术前 吉西他滨和白蛋白结合型紫杉醇。具体目标2：证明添加自噬抑制剂 羟氯喹将减少治疗肿瘤中的促存活途径。 证明PDA与DAMP诱导的过度系统性自噬状态相关。