An estimated 135,400 people developed colorectal cancer in the US in the year 2001 and 56,700 died of the disease. Despite some progress in developing better chemotherapy regimens and diagnostic methods, the 5-year survival rate in patients with colorectal cancer is only about 50 %, all stages included. A small but real decline in mortality from colorectal cancer over the last decade has been attributed to better screening. Colorectal cancer remains the third most common cause of cancer related death in the US. New understanding of the molecular pathways leading to the development and progression of colon cancer is enabling the development of more effective preventive agents for this common malignancy. ProlX Pharmaceuticals proposes to develop as a preventive agent for colorectal cancer, PX-12, a thioredoxin-1 (Trx-1) inhibitor, that we show inhibits several of the signaling pathways responsible for colon carcinogenesis. PX-12 has many characteristics required of a preventive agent. Its molecular target and mechanism of action are known, it is easy to manufacture and has good stability, it has an acceptable safety profile in humans and there is preliminary evidence for its preventive activity when administered orally in the ApcMin/+ mouse model of intestinal cancer. The goal of the proposed studies is to obtain preclinical evidence of the preventive activity of orally administered PX-12 and to demonstrate PX-12's ability to inhibit its molecular targets in animal models of colon carcinogenesis.
