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.
|Li, Changfeng; Zhang, Ying; Cheng, Xing et al. (2018) PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism. Dev Cell 46:441-455.e8|
|Boone, Brian A; Murthy, Pranav; Miller-Ocuin, Jennifer et al. (2018) Chloroquine reduces hypercoagulability in pancreatic cancer through inhibition of neutrophil extracellular traps. BMC Cancer 18:678|
|Song, Xinxin; Zhu, Shan; Xie, Yangchun et al. (2018) JTC801 Induces pH-dependent Death Specifically in Cancer Cells and Slows Growth of Tumors in Mice. Gastroenterology 154:1480-1493|
|Kang, Rui; Xie, Yangchun; Zhang, Qiuhong et al. (2017) Intracellular HMGB1 as a novel tumor suppressor of pancreatic cancer. Cell Res 27:916-932|
|Goding, Stephen R; Yu, Shaohong; Bailey, Lisa M et al. (2017) Adoptive transfer of natural killer cells promotes the anti-tumor efficacy of T cells. Clin Immunol 177:76-86|
|Zhu, Shan; Zhang, Qiuhong; Sun, Xiaofan et al. (2017) HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells. Cancer Res 77:2064-2077|
|Xie, Yangchun; Zhu, Shan; Song, Xinxin et al. (2017) The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity. Cell Rep 20:1692-1704|
|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|
|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|
Showing the most recent 10 out of 20 publications