Targeting Androgen Receptor-Driven Resistance to CYP17A1 Inhibitors
Technical Report,21 Aug 2014,20 Aug 2016
Health Research Inc. Buffalo United States
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Castration-recurrent prostate cancer CR-CaP represents the greatest cause of CaP-associated mortality due to its resistance to standard chemo- and radiotherapies that are efficacious against primary, androgen sensitive AS-CaP. CR-CaP progresses to metastatic disease in local lymph nodes and bone in the absence of serum androgen levels. Two recently FDA-approved drugs, abiraterone ABI and enzalutamide ENZ, have shown clinical efficacy against CR-CaP, yet drug resistance readily occurs within months of treatment, severely limiting clinical benefit. This validates these drugs and their targets in CR-CaP, however, knowledge regarding the mechanism underlying ABI- and ENZ-resistance will greatly benefit CR-CaP patients by producing better long-term efficacy of these drugs as well as next generation versions. The current proposal aims at directly dissecting the molecular mechanism underlying ABI and ENZ resistance in CRCaP. This is based on recent data showing that a shortened variant of the androgen receptor AR protein, called AR-V, is directly responsible for malignancy of CR-CaP, and moreover, that ENZ or ABI treatment actually enhances production of AR-V, leading to more drug resistance. We plan to isolate the AR gene sequence responsible for enhancing AR-V production using a novel molecular genetic technique, and then to identify the enhancer-binding proteins that drive enhancer activity, with the long-term aim to prevent ENZABI resistance by interrupting this interaction with small molecule inhibitors. Thus, this project is very timely and novel, and its findings will have a major benefit to CR-CaP patients by identifying pathways to enhance ENZ and ABI targets.
- Medicine and Medical Research