Abstract

Pancreatic cancer is the fourth leading cause of death from cancer in the United States. It has the worst survival of any malignancy followed in the S.E.E.R. database. The discovery of new targets present in pancreatic cancer cells is critically important, both for the prevention and for the treatment of pancreatic cancer. In this proposal, we describe a new target, aurora kinase, a key regulator of chromosome segregation present in pancreatic cancer cells which, with additional work, we feel can be used to develop new therapies for patients with the disease. Aurora kinases are members of the serine/threonine kinase superfamily. They have transforming capacities (are oncogenes) and are present in a variety of human tumors (particularly pancreatic cancer). In preliminary work, we have documented that aurora kinase is upregulated in all pancreatic cancer cell lines but not in normal pancreatic ductal cells. In addition, it is upregulated in pancreatic cancer taken directly from patients and is also amplified in some patients' tumors. This preliminary information makes aurora kinase a very attractive new target in pancreatic cancer.
The specific aims of this proposal are: 1. To further validate aurora kinase as a target in pancreatic cancer. The hypothesis is that aurora kinase is an important target in patients' pancreatic cancer cells. 2. To design agents which interfere with the activity of aurora kinase. The hypothesis is that agents can be found which can selectively inhibit the kinase. Two special techniques will be used to generate lead agents. As will be seen in the proposal, we have a lead from which to begin our design work. 3. To perform in vitro and in vivo testing of agents which interact with aurora kinase to select an agent which would be a candidate for clinical trials in patients with advanced pancreatic cancer. The hypothesis is that we can discover inhibitors of aurora kinase which can inhibit growth (or cause apoptosis) of pancreatic cancer cells both in vitro and in vivo. Aurora kinase has considerable potential to be a very important target in patients' pancreatic cancers, against which new therapeutics can be designed and developed.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095031-02
Application #
6622912
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Arya, Suresh
Project Start
2002-05-01
Project End
2007-04-30
Budget Start
2003-05-27
Budget End
2004-04-30
Support Year
2
Fiscal Year
2003
Total Cost
$303,379
Indirect Cost

  Institution

Name
University of Arizona
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721

  Publications

Whatcott, Clifford; Han, Haiyong; Posner, Richard G et al. (2013) Tumor-stromal interactions in pancreatic cancer. Crit Rev Oncog 18:135-51
Xie, Lifang; Kassner, Michelle; Munoz, Ruben M et al. (2012) Kinome-wide siRNA screening identifies molecular targets mediating the sensitivity of pancreatic cancer cells to Aurora kinase inhibitors. Biochem Pharmacol 83:452-61
Hidalgo, Manuel; Von Hoff, Daniel D (2012) Translational therapeutic opportunities in ductal adenocarcinoma of the pancreas. Clin Cancer Res 18:4249-56
Warner, Steven L; Stephens, Bret J; Nwokenkwo, Stanley et al. (2009) Validation of TPX2 as a potential therapeutic target in pancreatic cancer cells. Clin Cancer Res 15:6519-28
Warner, Steven L; Munoz, Ruben M; Bearss, David J et al. (2008) Pdx-1-driven overexpression of aurora a kinase induces mild ductal dysplasia of pancreatic ducts near islets in transgenic mice. Pancreas 37:e39-44
Warner, Steven L; Munoz, Ruben M; Stafford, Phillip et al. (2006) Comparing Aurora A and Aurora B as molecular targets for growth inhibition of pancreatic cancer cells. Mol Cancer Ther 5:2450-8
Warner, Steven L; Gray, Phillip J; Von Hoff, Daniel D (2006) Tubulin-associated drug targets: Aurora kinases, Polo-like kinases, and others. Semin Oncol 33:436-48
Rojanala, Sangeeta; Han, Haiyong; Munoz, Ruben M et al. (2004) The mitotic serine threonine kinase, Aurora-2, is a potential target for drug development in human pancreatic cancer. Mol Cancer Ther 3:451-7
Mahadevan, Daruka; Bearss, David J; Vankayalapati, Hariprasad (2003) Structure-based design of novel anti-cancer agents targeting aurora kinases. Curr Med Chem Anticancer Agents 3:25-34
Vankayalapati, Hariprasad; Bearss, David J; Saldanha, Jose W et al. (2003) Targeting aurora2 kinase in oncogenesis: a structural bioinformatics approach to target validation and rational drug design. Mol Cancer Ther 2:283-94

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