Chemoprevention by a Targeted Thioredoxin Inhibitor.

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DESCRIPTION (provided by applicant): Many of the molecular targets for the prevention of early cancer and for the therapy of advanced cancer are the same. Therefore, a logical place to seek new preventive agents is among the targeted therapeutic agents used for therapy of advanced cancer where their toxicity for human subjects is already known. We have developed a novel molecularly targeted therapeutic agent PX-12 (2-methylpropyl 2-imidazolyl disulfide) as an inhibitor of the redox signaling protein thioredoxin-1 (Trx-1). PX-12 has completed Phase I clinical trial against advanced tumors showing tumor regression and stable disease in a number of patients, and is now entering Phase II trial. Most importantly PX-12 is very well tolerated by patients with minimal toxicity. Trx-1 is over expressed in a wide variety of early and advanced human cancers including colon, gastric, pancreatic, breast, lung and skin cancer. In animal models elevated Trx-1 leads to increased sensitivity to carcinogens, increased tumor growth, resistance to apoptosis and increased tumor angiogenesis. In patient tumors elevated Trx-1 is associated with aggressive tumor growth, decreased apoptosis and decreased patient survival. We show that in the ApcMin/+ (multiple intestinal neoplasia) mouse model that mimics human familial adenomatous polyposis(FAP), PX-12 produces a marked decrease in the size and number of intestinal tumors, more effectively than the currently approved agent celecoxib . Thus, the hypothesis upon which our work is based is that Trx-1 imparts anti-death and pro-growth-signals in early cancer, thus, representing a novel target for chemoprevention, and that the Trx-1 inhibitor PX-12 will be an effective agent for the prevention of colon cancer and other human cancers. The objectives of the proposed studies are to conduct mechanistic investigations on the effects of PX-12, to obtain preclinical evidence for the preventive activity of orally administered PX-12 against colon and breast cancers, to demonstrate PX-12's ability to inhibit its molecular target(s) in the animal models of chemoprevention, and to provide evidence for the mechansim of PX-12's chemopreventive activity. Our overall goal is to obtain the information necessary for the clinical development of PX-12 as a molecularly targeted preventive agent for patients at high risk or with early disease. PUBLIC HEALTH RELEVANCE A logical place to seek new cancer preventive drugs is among the agents used for the therapy of advanced cancer where the toxicity for human subjects is already known. We have developed a novel therapeutic agent PX-12 as an inhibitor of the cancer causing protein thioredoxin-1. PX-12 has recently completed a Phase I clinical trial in patients with advanced cancer showing little toxicity and with antitumor activity. The objective of the proposed studies is to obtain preclinical evidence for the cancer preventive activity of PX-12 against early colon and breast cancer. The information obtained will be used for the clinical development of PX-12 as a cancer preventive agent for patients at high risk or with early disease.