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.
|Krasnoslobodtsev, Alexey V; Torres, María P; Kaur, Sukhwinder et al. (2015) Nano-immunoassay with improved performance for detection of cancer biomarkers. Nanomedicine 11:167-73|
|Kaur, Sukhwinder; Sharma, Neil; Krishn, Shiv Ram et al. (2014) MUC4-mediated regulation of acute phase protein lipocalin 2 through HER2/AKT/NF-*B signaling in pancreatic cancer. Clin Cancer Res 20:688-700|
|Liu, Xiang; Yi, Chunhui; Wen, Yunfei et al. (2014) Interactions between MUC1 and p120 catenin regulate dynamic features of cell adhesion, motility, and metastasis. Cancer Res 74:1609-20|
|Momi, Navneet; Kaur, Sukhwinder; Rachagani, Satyanarayana et al. (2014) Smoking and microRNA dysregulation: a cancerous combination. Trends Mol Med 20:36-47|
|Kane, Daniel P; Shcherbakova, Polina V (2014) A common cancer-associated DNA polymerase ? mutation causes an exceptionally strong mutator phenotype, indicating fidelity defects distinct from loss of proofreading. Cancer Res 74:1895-901|
|Stark, Jaime L; Mehla, Kamiya; Chaika, Nina et al. (2014) Structure and function of human DnaJ homologue subfamily a member 1 (DNAJA1) and its relationship to pancreatic cancer. Biochemistry 53:1360-72|
|Mehla, Kamiya; Singh, Pankaj K (2014) MUC1: a novel metabolic master regulator. Biochim Biophys Acta 1845:126-35|
|Mimeault, Murielle; Batra, Surinder K (2014) Molecular biomarkers of cancer stem/progenitor cells associated with progression, metastases, and treatment resistance of aggressive cancers. Cancer Epidemiol Biomarkers Prev 23:234-54|
|Kaur, Sukhwinder; Momi, Navneet; Chakraborty, Subhankar et al. (2014) Altered expression of transmembrane mucins, MUC1 and MUC4, in bladder cancer: pathological implications in diagnosis. PLoS One 9:e92742|
|Dey, Parama; Rachagani, Satyanarayana; Vaz, Arokia P et al. (2014) PD2/Paf1 depletion in pancreatic acinar cells promotes acinar-to-ductal metaplasia. Oncotarget 5:4480-91|
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