Pancreatic cancer is a major cause of cancer-related deaths in the United States, and it is estimated that over 30,000 new cases will be diagnosed in 2003. Pancreatic cancer is usually not detected until this tumor has progressed or metastasized, and the mean survival time for metastatic disease is 3 to 6 months. There is clearly an urgent need to develop early markers for this cancer and new agents for treatment of this aggressive disease. Several studies have shown that Peroxisome Proliferator-activated receptor gamma (PPARgamma) is expressed in multiple tumor types, and PPARgamma agonists inhibit growth of pancreatic cancer cells. Studies in this laboratory have identified a series of 1,1-bis (3'-indolyl)-1- (p-substituted phenyl) methanes [methylene or C-substituted diindolylmethanes (DIMs)] that are relatively non-toxic and exhibit PPAR gamma agonist activity. Preliminary studies show that PPARgamma -Active C-substituted DIMs inhibit growth of pancreatic cancer cells in vitro, and tumor growth inhibition by these compounds is also observed in athymic nude mice bearing Panc-1 pancreatic cancer cell xenografts. The proposed studies in this grant application will focus on development of PPARgamma -Active C-substituted DIMs as a new class of drugs for treatment of pancreatic cancer and includes the following specific aims.
Aim 1 will determine structure-activity relationships among a series of C-substituted DIMs to identify the most active compounds in a series of transactivation, differentiation, cell proliferation, and cell cycle progression assays.
In Aim 2, the most active PPARgamma agonists characterized in Aim 1 will serve as models for identifying the key cell cycle regulatory genes targeted by PPARgamma in six pancreatic cancer cell lines. Moreover, based on results of preliminary studies with PPARgamma -active C-substituted DIMs, detailed mechanistic studies on the down-regulation of cyclin D1 and upregulation of p21 by PPARgamma agonists will be carried out.
In Aim 3, the in vivo anticarcinogenic activities of PPARgamma -active C-substituted DIMS will be investigated using athymic nude mice bearing pancreatic cancer cell xenografts. The proposed research will identify the most potent PPAR? -active C-substituted DIMs that inhibit pancreatic cancer cell growth in vitro and in vivo, and these will serve as lead compounds for development of new drugs for clinical treatment of this devastating disease
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