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 enhaces 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 treateing 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.

Public Health Relevance

The research proposed in this project will explore the capacity of a new class of molecules that inhibit the activity of CDK5 in pancreatic cancer. These inhibitors have the potential to inhibit disease progression in premalignant and malignant lesions, and tumor associated pain. If successful these inhibitors will benefit every type of pancreatic cancer patient including those that have failed other therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Medical Center
United States
Zip Code
Krasnoslobodtsev, Alexey V; Torres, MarĂ­a 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

Showing the most recent 10 out of 73 publications