Plasmin-activated Prodrug Therapy for Pancreatic Cancer

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer related deaths and the median survival time after diagnosis is only five months. The disease is generally metastatic with limited treatment options. Research is proposed to evaluate in vivo a newly designed, targeted, prodrug therapy for pancreatic cancer that should be effective against metastatic and resistant disease. The therapy is based upon the active metabolite of the antitumor drug doxorubicin, which is an order of magnitude more active against pancreatic cancer cells than doxorubicin and is active against a wide variety of both sensitive and resistant cancer cells. Targeting is achieved through activation by the enzyme plasmin, overexpressed by many cancer cells, including pancreatic cancer cells, and their associated angiogenesis. The drug is inactive until cleaved by plasmin that is created at the cell surface by hydrolysis of plasminogen. Critical to specificity is inactivation of plasmin that escapes to the vascular system by circulating antiplasmins. The therapy is designed to maximize efficacy and minimize side effects including cardiotoxicity. Experiments are proposed to evaluate the therapy in a nude mouse model of pancreatic cancer and to evaluate systemic toxicity including cardiotoxicity in a rat model.