This application for a Specialized Program of Research Excellence in Pancreatic Cancer focuses on translational studies that address basic and clinical issues of importance to improving the outcome of patients with pancreatic cancer. Specifically, the research projects in this program seek to: 1) develop and test novel therapeutic strategies including chemotherapy, and chemoradiation therapy for patients with early and advanced pancreatic cancer;2) undertake basic research studies in conjunction with clinical trials that will provide insight at the molecular level into the reasons for success and failure of the different strategies. The first project investigates potential of novel inhibitors of CDKS to block tumor progression and nociceptive signaling (pain) in preclinical animal models and in a phase I clinical trial in patients that have failed other therapies. The second project investigate further the molecular nature of radioresistance in patients with borderline resectable disease and proposes a clinical trial with inhibitors of the cholesterol synthesis pathway (Zometa) as a therapeutic intervention. The third project investigates therapeutic strategies that may be effective in SMAD4 mutant and SMAD4 wildtype tumors and proposes a novel clinical trial with a combination of an HDAC inhibitor (Belinostat) and an inhibitor to surviving (YM155) in patients that have failed other therapies. The fourth project investigates the possibility that a hypoxic an desmoplastic environment in pancreatic cancer affects metabolic features of the tumor and stroma that result in high endogenous production of cytidine, which in turn causes drug resistance to fluropyrimidines. Two therapeutic strategies that inhibit hypoxia (digoxin) and pyrimidine biosynthesis (leflunomide) will be investigated in a clinical trial, and the possibility that cytidine and associated metabolites can serve as biomarkers of drug resistance will be investigated. Our tissue core proposes to continue its unique collection of metastatic tumor samples through our rapid autopsy program, in addition to capturing samples associated with surgical resections. All projects are supported by administrative and biostatistics cores.

Public Health Relevance

This application for a Specialized Program of Research Excellence in Gastrointestinal (Pancreatic Cancer) will focus on translational studies that address basic and clinical issues of importance to improving the outcome of patients with pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA127297-06A1
Application #
8738887
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Program Officer
Agarwal, Rajeev K
Project Start
2008-09-05
Project End
2019-08-31
Budget Start
2014-09-23
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
$2,162,000
Indirect Cost
$725,455
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Attri, Kuldeep S; Murthy, Divya; Singh, Pankaj K (2017) Racial disparity in metabolic regulation of cancer. Front Biosci (Landmark Ed) 22:1221-1246
Wu, Guangyin; Verma, Vivek; Haefner, Matthias F et al. (2017) Feasibility and reproducibility of substituting oral contrast with water for duodenal volume delineation in patients undergoing pancreatic stereotactic body radiotherapy. J Gastrointest Oncol 8:705-709
Verma, Vivek; Lazenby, Audrey J; Zheng, Dandan et al. (2017) Dosimetric parameters correlate with duodenal histopathologic damage after stereotactic body radiotherapy for pancreatic cancer: Secondary analysis of a prospective clinical trial. Radiother Oncol 122:464-469
Karmakar, Saswati; Seshacharyulu, Parthasarathy; Lakshmanan, Imayavaramban et al. (2017) hPaf1/PD2 interacts with OCT3/4 to promote self-renewal of ovarian cancer stem cells. Oncotarget 8:14806-14820
Shukla, Surendra K; Purohit, Vinee; Mehla, Kamiya et al. (2017) MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer. Cancer Cell 32:71-87.e7
King, Ryan J; Yu, Fang; Singh, Pankaj K (2017) Genomic alterations in mucins across cancers. Oncotarget :
Krishn, Shiv Ram; Kaur, Sukhwinder; Sheinin, Yuri M et al. (2017) Mucins and associated O-glycans based immunoprofile for stratification of colorectal polyps: clinical implication for improved colon surveillance. Oncotarget 8:7025-7038
Gautam, Shailendra K; Kumar, Sushil; Cannon, Andrew et al. (2017) MUC4 mucin- a therapeutic target for pancreatic ductal adenocarcinoma. Expert Opin Ther Targets 21:657-669
Abrego, Jaime; Gunda, Venugopal; Vernucci, Enza et al. (2017) GOT1-mediated anaplerotic glutamine metabolism regulates chronic acidosis stress in pancreatic cancer cells. Cancer Lett 400:37-46
Souchek, Joshua J; Davis, Amanda L; Hill, Tanner K et al. (2017) Combination Treatment with Orlistat-Containing Nanoparticles and Taxanes Is Synergistic and Enhances Microtubule Stability in Taxane-Resistant Prostate Cancer Cells. Mol Cancer Ther 16:1819-1830

Showing the most recent 10 out of 163 publications