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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的胰腺导管腺癌是一种过度自噬的疾病。胰腺导管腺癌（PDA）是一种高度致命的疾病，其特征是早期全身性传播、生物能学扰动、炎症、凝血和化疗耐药。一个临床医生和科学家一直未能找到解释这些肿瘤相关紊乱的共同联系。在通过基因工程小鼠模型的人类胰腺癌，我们已经证明 IL-6 介导由损伤相关分子模式蛋白 (DAMP) 诱导的自噬是最终的生存关键肿瘤微环境中促进癌发生、肿瘤进展和耐药的途径治疗。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 是一个系统性的 DAMP 紊乱导致过度自噬。成功的治疗将与康复相关稳态基础自噬。在这里，我们建议通过执行一项试验来直接解决患者的这一假设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。我们最近完成了两项术前试验的“原理证明”试验吉西他滨/羟氯喹和吉西他滨/白蛋白结合型紫杉醇；论证可行性、安全性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项临床试验中研究以下具体目标：具体目标 I：证明添加自噬抑制剂羟氯喹可改善术前反应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相关。