Poor prognosis in pancreatic cancer is due in part to poor response to the current standard of care (gemcitabine, a cytidine nucloeside analog). Our preliminary data establish a novel, widely-prevalent mechanism of resistance to fluoropyrimidines whereby the Hypoxia-Inducible Factor1 (HIF1) alpha-induced glycolytic flux leads to a corresponding increase in the pyrimidine biosynthetic pathway to enhance the intrinsic levels of cytidine. Such increased levels of cytidine/dCTP diminish the effective levels of gemcitabine and 5FU (in FOLFIRINOX) through molecular competition or dilution. Our data also indicate existance of a bidirectional tumor-stromal metabolite flux that may facilitate tumor/stromal cell survival under low nutrient conditions, promote desmoplasia, increase metabolite flux into pyrimidine biosynthetic pathway, and result in decreased chemotherapy sensitivity. Thus, we propose to determine if combining gemcitabine/FOLFIRINOX therapies with digoxin (to target HIF1 alpha) or Leflunomide (to target pyrimidine biosynthesis) will diminish fluoropyrimidine therapy resistance in pancreatic cancer patients (AIM 1). Additionally, we will employ 18FFDG- PET imaging in pancreatic cancer patients to predict the resistance status of the tumor against pyrimidine analogs (AIM1). We will also investigate if cytidine levels in pancreatic tumors/biofluids may serve as potential biomarkers for chemotherapy responsiveness in pancreatic cancer patients (AIM2). Furthermore, we will investigate if tumor-stromal metabolite exchange facilitates stromal cell survival and desmoplasia in tumor models, and increased pyrimidine biosynthesis and diminished gemcitabine responsiveness in tumor cells (AIM3). We predict that our proposed improvement to current chemotherapy strategies will improve survival in pancreatic cancer patients by increasing the efficacy and/or decreasing the toxicity, by requiring smaller doses, of chemotherapy strategies that employ gemcitabine and/or 5FU.
Here, we will investigate if targeting a novel metabolic pathway of chemoresistance will be efficacious in improving responsiveness to fluoropyrimidine-based therapies in pancreatic tumors. We will investigate imaging/biomarker approaches for predicting response and determine if novel combinations of approved chemotherapy agents with gemcitabine or FOLFIRINOX will improve survival in pancreatic cancer.
|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|
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