Development of a CES 2-Activated Doxazolidine Prodrug for Pancreatic Cancer

University Of Colorado, Boulder CO

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Abstract

DESCRIPTION (provided by applicant): Pancreatic cancer is one of the most common causes of cancer-related deaths in spite of its relatively low occurrence, and new therapies are needed, especially ones that address resistance. Research is proposed to evaluate in vivo a newly designed, targeted, prodrug therapy for cancers that overexpress the carboxylesterase, CES2, with focus on pancreatic cancer. The therapy is based upon doxazolidine, a formaldehyde conjugate of doxorubicin that is more than an order of magnitude more active against a variety of both sensitive and resistant (MDR phenotype) cancer cells than doxorubicin. Doxazolidine induces cancer cell death by a different mechanism and is less toxic to cardiomyocytes than doxorubicin. The prodrug of doxazolidine, N-(pentyloxycarbonyl-p-aminobenzyloxycarbonyl)doxazolidine (pentyl PABC- Doxaz, PPD), is activated by CES2 in pancreas, liver, lung and kidney cancer cells amongst other cancer cells. The drug is inactive until cleaved by CES2. Critical to specificity is stability in human plasma predicting stability in the vascular system. The therapy is designed to maximize efficacy and minimize side effects including cardiotoxicity. Very little CES2 is expressed in rat cardiomyocytes and the prodrug is two orders of magnitude less toxic to rat cardiomyocytes than doxorubicin. A drug delivery strategy that utilizes enhanced permeability and retention (EPR) effect is also proposed to maximize efficacy and minimize side effects. Experiments are designed to evaluate the therapy in an orthotopic mouse model of pancreatic cancer and to evaluate systemic toxicity including cardio and liver toxicity in a rat model. Preliminary subcutaneous xenograft experiments indicate tumor growth inhibition without significant side effects in mouse models of liver cancer and non-small cell lung cancer using cancer cells that express CES2. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is one of the most frequent causes of cancer-related deaths in Western industrialized countries (9 to 10 cases / 100,000 population) because it is often asymptomatic at early stages and aggressive, metastatic, and resistant upon diagnosis at later stages. Research is proposed to evaluate in vivo a newly designed, targeted therapeutic for pancreatic cancer that should be effective against metastatic and resistant disease with minimal side effects.