The poor response of existing treatnnent options for unresectable pancreatic cancer is the result of a subset of cancer cells exhibiting chemoresistance. Evidence has shown that the capacity of a tumor to grow and propagate is dependent on this small subset of cells, identified as pancreatic cancer stem (or stem-like) cells (CSCs). Due to their vital role in tumor maintenance and the formation of metastases, CSCs are integral targets to treat pancreatic cancer, as current therapeutic regimens cannot effectively treat this cell population because of its intrinsically resistant nature. Adenovirus (Ad)-based oncolytic viruses have unique advantages for targeting and eradicating pancreatic CSCs along with inclusively targeting the general pancreatic cancer cell population and thereby represent a promising novel therapeutic strategy. Ad replication specificity can be achieved by placing viral replication genes under the control of tumor-specific promoters, thereby generating conditionally replicative adenoviruses (CRAds). The keys to developing a pancreatic cancer CRAd that inclusively targets CSCs are: 1) effective transduction and 2) replication specificity of pancreatic cancer cells and CSCs. We have developed innovative strategies and breakthrough technologies which can be rapidly applied for designing such CRAds. Our advanced infectivity enhancement strategies allow efficient transduction of pancreatic cancer cells and CSCs. To confer replication specificity, we have developed the CXCR4 promoter as a CRAd replication control element. CXCR4 expression Is a signature of pancreatic cancer and CSCs. SA 1: To construct infectivity-enhanced, CXCR4 promoter controlled CRAds for pancreatic cancer, inclusively targeting pancreatic CSCs. SA 2: To validate the efficacy of CRAds with in vitro models of chemoresistant pancreatic CSCs. SA 3: To demonstrate efficacious targeting and replication of CXCR4 CRAds with in vivo models of pancreatic cancer. SA 4: To validate the efficacy and specificity of pancreatic CSC-targeted CRAds with primary CSCs derived from human patient tumors. Development of an effective therapy for the advanced pancreatic cancer Is predicated on efficiently targeting and eradicating pancreatic CSCs, which represent the chemoresistant nature of this disease. The strategy proposed herein, of exploiting CRAd agents based on the CXCR4 axis to inclusively target pancreatic CSCs offers a promising treatment approach. On the basis of these studies, we will thus understand the direct utility of our novel system for clinical application and will facilitate a rapid clinical translation. We will submit an IND application concurrently with this proposal to rapidly translate the agents herein for clinical trial.

Public Health Relevance

Development of an effective therapy for the treatment of advanced pancreatic cancer is predicated on efficiently targeting and eradicating pancreatic cancer stem cells (CSCs), which represent the chemoresistant nature of this disease. Recent advances in adenovirus (Ad)-based oncolytic virus design allow the application of Ad vectors as a therapeutic strategy to efficiently target and eradicate pancreatic nSCs therehv imnrnvina the efficacv nf nannreatic cancer treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Alabama Birmingham
United States
Zip Code
Roe, Jae-Seok; Hwang, Chang-Il; Somerville, Tim D D et al. (2017) Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis. Cell 170:875-888.e20
Feigin, Michael E; Garvin, Tyler; Bailey, Peter et al. (2017) Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma. Nat Genet 49:825-833
Chio, Iok In Christine; Tuveson, David A (2017) ROS in Cancer: The Burning Question. Trends Mol Med 23:411-429
Öhlund, Daniel; Handly-Santana, Abram; Biffi, Giulia et al. (2017) Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med 214:579-596
Zhong, Yi; Macgregor-Das, Anne; Saunders, Tyler et al. (2017) Mutant p53 Together with TGF? Signaling Influence Organ-Specific Hematogenous Colonization Patterns of Pancreatic Cancer. Clin Cancer Res 23:1607-1620
Contreras, Carlo M; Lin, Chee Paul; Oster, Robert A et al. (2017) Increased pancreatic cancer survival with greater lymph node retrieval in the National Cancer Data Base. Am J Surg 214:442-449
Kim, Harrison; Buchsbaum, Donald J; Zinn, Kurt R (2016) A Novel Imaging Biomarker Extracted from Fluorescence Microscopic Imaging of TRA-8/DR5 Oligomers Predicts TRA-8 Therapeutic Efficacy in Breast and Pancreatic Cancer Mouse Models. Mol Imaging Biol 18:325-33
Reddy, Sushanth; Contreras, Carlo M; Singletary, Brandon et al. (2016) Timed Stair Climbing Is the Single Strongest Predictor of Perioperative Complications in Patients Undergoing Abdominal Surgery. J Am Coll Surg 222:559-66
Ho, Yen-Yi; Guan, Weihua; O'Connell, Michael et al. (2016) Powerful association test combining rare variant and gene expression using family data from Genetic Analysis Workshop 19. BMC Proc 10:251-255
Malfatti, Michael A; Kuhn, Edward A; Turteltaub, Kenneth W et al. (2016) Disposition of the Dietary Mutagen 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline in Healthy and Pancreatic Cancer Compromised Humans. Chem Res Toxicol 29:352-8

Showing the most recent 10 out of 166 publications