AKR1C3 AS A BIOMARKER, METHODS OF SELECTING AND TREATING PATIENTS BASED UPON AN AKR1C3 PROFILE AND COMPOUNDS FOR USE THEREIN

摘要

The invention is based on the finding that the enzyme AKR1C3 is capable of exhibiting nitroreductase activity and activating nitroaromatic prodrugs to release the cytotoxic effector. AKR1C3-activated nitroaromatic prodrugs include dinitrobenzamide mustards such as 2-((2-bromoethyl)-2-{[(2-hydroxyethyl)amino]carbonyl}-4,6-dinitroanilino)ethyl methanesulfonate (PR-104A), and the corresponding pre-prodrug 2-[(2-(bromoethyl)-2,4-dinitro-6-[[[2- (phosphonooxy)ethyl]amino]carbonyl]anilino]ethyl methanesulfonate (PR-104). The invention provides methods and procedures to determine drug sensitivity in patients to allow the identification of individualized patient profiles which will aid in treating diseases and disorders, such as cancer. The invention also provides methods of treatment which are based upon such biomarker-related profiles, as well as compounds suitable for use in such methods and compositions comprising "such compounds.