Pancreatic SPORE

Project Leaders:  Michael A. Hollingsworth, PhD, and Jean Grem, MD.

The project presented evidence that the inhibition of CDK5 with a 3, 5-disubstituted pyrazole significantly reduces tumor size, metastasis, and vascularization of pancreatic tumors growing as xenografts in nude mice. We studied the effects of CDK5 inhibition on pancreatic adenocarcinoma progression in two distinct mouse models that recapitulate the human disease as it progresses from pancreatitis to PanIN lesions and from PanIN formation through metastasis. This study focused on inhibiting CDK5 alone during early disease development and evaluate the therapeutic capacity of inhibiting CDK5 in later disease progression, using the inhibitor and Gemcitabine-Abraxane. A second benefit of inhibiting CDK5 is that it reduces pain, given its role in nociceptive signaling. Consequently, we also undertook preclinical studies to determine if CDK5 inhibition blocks pain associated with pancreatitis and tumor growth.

Project Leaders:  Surinder Batra, PhD, and Chi Lin, MD.

This project's objective was to identify and characterize pathways contributing to radioresistance in pancreatic cancer that could be explored as novel targets for radiosensitization. Preliminary global gene expression analysis suggested novel involvement of cholesterol biosynthesis pathway in the radioresistance in pancreatic cancer cells. Inhibition of cholesterol biosynthesis by Zoledronic acid (Zometa) resulted in radiosensitization of panel of radioresistance murine and human pancreatic cancer cells. This radiosensitization was recapitulated by the inhibition of the small GTPase Rac1, whose activity is controlled by the cholesterol biosynthesis pathway. Therefore, we sought to delineate mechanisms of radioresistance mediated by cholesterol biosynthesis pathway, and evaluate the potential of Zometa as a radiosensitizer in preclinical and clinical studies. We proposed to exploit the strength of stereotactic radiation therapy and genetically engineered mouse models to comprehensively test the hypothesis that “cholesterol biosynthesis pathway contributes to radioresistance and Zometa inhibits specific pathways consistently implicated in radioresistance and its use will radiosensitize pancreatic cancer cells both in vitro and in vivo.” 

Project Leaders:  Jennifer Black, PhD, and Quan Ly, MD.

This project addressed the poor survival rate of pancreatic cancer patients through the development of  therapeutic strategies for drug treatment based on the targeting of newly identified molecules as targets for maintaining the survival of pancreatic cancer cells using emerging novel drugs. We tested these emerging drugs in human pancreatic cancer cells grown in immunosuppressed mice to demonstrate the feasibility that effective combination strategies tailored for the Smad4 wild type and mutant subgroups of pancreatic cancer, respectively, can be developed.

Project Leaders:  Pankaj Singh, PhD, and Jean Grem, MD.

This project's objective was to to determine if combining gemcitabine/FOLFIRINOX therapies with digoxin (to target hypoxia-inducible factor1 alpha-induced glycolytic flux) or Leflunomide (to target pyrimidine biosynthesis) would diminish fluoropyrimidine therapy resistance in pancreatic cancer patients. Additionally, we employed 18FFDG-PET imaging in pancreatic cancer patients to predict the resistance status of the tumor against pyrimidine analogs. We also investigated if cytidine levels in pancreatic tumors/biofluids could serve as potential biomarkers for chemotherapy responsiveness in pancreatic cancer patients.