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.
Adenocarcinoma of the pancreas is expected to be the fourth leading cause of cancer deaths in the United States in 2013. Five year survival is less than 5% and mortality rates are nearly identical to its incidence. We hypothesize that progression and resistance to therapeutic intervention in adenocarcinoma of the pancreas is promoted by HMGB1/RAGE signaling leading to a perpetual state of increased autophagy and resistance to apoptosis. In this proposal we will validate targeting this novel molecular pathway (HMGB1/RAGE) neo- adjuvant clinical trial. The results of this project will provide important preclinical and clinical information that will directly drive future bench-top and bedside studies.
|Kang, Rui; Xie, Yangchun; Zhang, Qiuhong et al. (2017) Intracellular HMGB1 as a novel tumor suppressor of pancreatic cancer. Cell Res 27:916-932|
|Zhu, Shan; Zhang, Qiuhong; Sun, Xiaofan et al. (2017) HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells. Cancer Res 77:2064-2077|
|Kaltenmeier, Christof T; Vollmer, Laura L; Vernetti, Lawrence A et al. (2017) A Tumor Cell-Selective Inhibitor of Mitogen-Activated Protein Kinase Phosphatases Sensitizes Breast Cancer Cells to Lymphokine-Activated Killer Cell Activity. J Pharmacol Exp Ther 361:39-50|
|Song, Xinxin; Zhu, Shan; Xie, Yangchun et al. (2017) JTC801 Induces pH-dependent Death Specifically in Cancer Cells and Slows Growth of Tumors in Mice. Gastroenterology :|
|Lotfi, Ramin; Kaltenmeier, Christof; Lotze, Michael T et al. (2016) Until Death Do Us Part: Necrosis and Oxidation Promote the Tumor Microenvironment. Transfus Med Hemother 43:120-32|
|Kang, Rui; Chen, Ruochan; Xie, Min et al. (2016) The Receptor for Advanced Glycation End Products Activates the AIM2 Inflammasome in Acute Pancreatitis. J Immunol 196:4331-7|
|Ganguli, Mary; Lotze, Michael T (2015) Parkinson Disease and Malignant Disease: Minding Cancer's Own Business. JAMA Oncol 1:641-2|
|Boone, Brian A; Bahary, Nathan; Zureikat, Amer H et al. (2015) Safety and Biologic Response of Pre-operative Autophagy Inhibition in Combination with Gemcitabine in Patients with Pancreatic Adenocarcinoma. Ann Surg Oncol 22:4402-10|
|Huang, Jin; Xie, Yangchun; Sun, Xiaofang et al. (2015) DAMPs, ageing, and cancer: The 'DAMP Hypothesis'. Ageing Res Rev 24:3-16|
|Chen, Ruochan; Fu, Sha; Fan, Xue-Gong et al. (2015) Nuclear DAMP complex-mediated RAGE-dependent macrophage cell death. Biochem Biophys Res Commun 458:650-5|
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