Aurora Kinase as a Therapeutic Target in Cancer

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DESCRIPTION (provided by applicant): 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.