Kinases are attractive drug targets as evidenced by the number of recent FDA approvals of kinase inhibitors for cancer therapy. The drugs currently in the clinics are against either overexpressed kinases or mutated kinases that are implicated in the disease. However not all druggable kinases are mutated or overexpressed in many cases their activity altered through post-translational modifications. Others and we have identified elevated levels of phosphorylated IKK in the tumor samples compared to the normal tissues suggesting that the diseased state of IKK exists phosphorylated state. IKK like other kinases is regulated by sequential phosphorylation-dephosphorylation events. The lack of phospho-specific antibodies against the various phosphorylated forms of IKK makes defining the diseased state a challenging endeavor. In this application we will use a novel technology NanoPro 1000 to address this issue in pancreatic tumors and cell lines. This is an exploratory project as we seek to characterize the various post-translational modifications associated with a disease relevant kinase. Our focus on the specific forms of IKK, rather than IKK in general, makes this bother novel and innovative.
Pancreatic cancer has a 5-year survival of ~6% and has not changed in the past 25 years. Studies with tumor specimens indicate the presence of TNF? in the tumor microenvironment in 50% of the samples and elevated levels of phosphorylated IKK in the tumor cells when compared to normal cells. In this application, we will use a novel technology NanoPro 1000 to characterize phosphorylated states of IKK? to define its diseased state in pancreatic tumors and cell lines.
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