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Last Updated: 11/07/17

UNIVERSITY OF NEBRASKA MEDICAL CENTER SPORE IN PANCREATIC CANCER

University of Nebraska

Principal Investigator:
Michael A. Hollingsworth, Ph.D.

Overall Abstract

This 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 CDK5 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 investigates 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 and 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.

This SPORE includes four projects.

Project 1: Inhibition of CDK5 as a Treatment for Pancreatic Cancer

Co-Project Leaders:
Michael A. Hollingsworth, Ph.D. and
Jean Grem, M.D.

Recent studies in our laboratory and others demonstrate that the CDK5 gene or its coactivators is amplified in a majority of human pancreatic cancers, expressed in all pancreatic cancer cell lines tested and that CDK5 activity increases as a consequence of the action of mutant k-Ras, which in turn enhances pancreatic cancer cell growth, invasion and metastasis. We present 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 propose to study 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 will focus 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 will also undertake preclinical studies to determine if CDK5 inhibition blocks pain associated with pancreatitis and tumor growth. We will also undertake a Phase I human clinical trials that evaluate the clinical utility of inhibiting CDK5 in advanced pancreatic cancer patients that have failed other therapy options. In the longer term these studies may enable Phase II clinical trials for treating pancreatitis and pancreatic cancer. We will also undertake parallel drug design studies to develop next-generation molecules that improve targeting of CDK5 in pancreatic cancer patients.

Project 2: Novel Target(s) in the Radiosensitization of Pancreatic Cancer

Co-Project Leaders:
Surinder Batra, Ph.D.
Chi Lin, M.D

Despite being a staple therapy for pancreatic cancer (PC), Radiation Therapy (RT) provides limited objective clinical response due to inherently high radioresistance (RR) of PC. As the risk of radiation-induced toxicity for PC patients far outweighs the therapeutic benefits attained, effective methods to improve the radiosensitivity of PC are urgently needed. The overall objective of this project is to identify and characterize pathway(s) contributing to RR in PC that can be explored as novel targets for radiosensitization (RS). Preliminary global gene expression analysis suggested novel involvement of cholesterol biosynthesis pathway in the RR in PC cells. Inhibition of cholesterol biosynthesis (CBS) by Zoledronic acid (Zometa) resulted in RS of panel of RR murine and human PC cells. Further, this RS was recapitulated by the inhibition of the small GTPase Rac1, whose activity is controlled by the CBS pathway. Therefore, we seek to delineate mechanisms of RR mediated by cholesterol biosynthesis pathway, and evaluate the potential of Zometa as a radiosensitizer (RST) in preclinical and clinical studies. We propose 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 in PC and Zometa inhibits specific pathways consistently implicated in RR and its use will radiosensitize PC both in vitro and in vivo". To achieve our goal, three specific aims are proposed. Aim 1 will elucidate the mechanisms of radioresistance in PC and validation of FDPS/Rac1 inhibitors (Zometa and NSC23766) as RSTs. The functional role of critical genes identified will be determined by knockdown and overexpression studies, use of specific inhibitors, and immunohistochemistry on clinical samples. Aim 2 will determine the efficacy of Zometa as RST in mouse models (xenograft and autochthonous). A novel strategy of stereotactic irradiation for murine models will be developed. In Aim 3, a Phase-I/II study will be undertaken to assess the radiosensitizing potential of Zometa in human subjects and determine if Zometa is well tolerated in PC patients undergoing RT.

Project 3: Novel Strategies for Pancreatic Cancer Treatment

Co-Project Leaders:
Jennifer Black, Ph.D.
Jing (Jenny) Wang, Ph.D.
Quan Ly, M.D.

Pancreatic cancer (PaCa) carries a poor survival due to lack of effective drug treatment. This project will address this barrier through the development of new therapeutic strategies for drug treatment of PaCa based upon the targeting of newly identified molecules as targets for maintaining the survival of PaCa cells using emerging novel drugs. We will test 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 (WT) and mutant (MT) subgroups of PaCa, respectively, can be developed. The strategies are based upon description of a cell survival mechanism in which a pro-survival protein complex consisting of survivin and XIAP inhibits the executioner caspase enzymes that would normally kill cancer cells under-going the stress of the cancer micro-environment. Our laboratory has found that the mutation of Smad4 leads to the overproduction of a cell surface protein called RonK that in turn generates the activation of enzymes that modify the survivin/XIAP complex to enhance its stability and thereby make the inhibition of caspases more efficient. Consequently, one arm of the strategy for the Smad4 MT subgroup (approximately 50% of PaCa) will be the inhibition of the Met family tyrosine kinase receptor RonK by a newly developed monoclonal antibody from Imclone (IMC-Ron8). Treatment will be coupled with YM155, a first-in-its-class inhibitor of survivin, which has been shown to disrupt the stabilization of survivin/XIAP complexes that then permits the function of caspases in generating cell death. The second subgroup is Smad4 WT, which represents the other half of the disease, will be addressed by a strategy that takes advantage of Smad4 function using a drug that cause re-expression of a tumor suppressor gene called TGFβ receptor II. The drug, Belinostat, a histone deacetylase inhibitor reverses the epigenetic signaling pathway that stabilizes both survivin and XIAP. The Smad4 WT subgroup will also be treated in combination with YM155 to directly attack the expression of survivin. Both strategies will be tested in immunosuppressed mice using pancreatic cancer xenografts in order to learn how best to administrate these drugs to pancreatic cancer patients.

Project 4: Targeting Metabolic Alterations to Improve Survival in Pancreatic Cancer

Co-Project Leaders:
Pankaj Singh, Ph.D.
Jean Grem, M.D.

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 existence 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.

The four projects are supported by three Cores:

Core A — Administration. Core Director: Michael A. Hollingsworth, PhD
Core B — Tissue. Core Director: Julia Bridge, MD
Core C — Biostatistics. Core Director: Fang Yu, PhD