Repression of the Androgen Receptor by WT1, a Tumor Suppressor Gene.

摘要

Androgen-independent prostate cancer responds poorly to conventional chemotherapeutic agents. This observation has prompted an aggressive search for the molecular mechanisms responsible for drug resistance in these cells and for new agents that specifically target or overcome these resistance mechanisms. The two Specific Aims of this proposal were directed at both of these important topics. In the first we proposed to identify the molecular mechanisms responsible for overexpression of BCL-2 and associated apoptosis resistance in androgen-independent variants of the human LNCaP prostate adenocarcinoma line selected for enhanced metastatic potential in vivo. The second Specific Aim focused on characterizing the activity and mechanisms of action of a new agent (PS-341) that was found to be capable of bypassing BCL-2-mediated cell death resistance in transfectants in vitro. Our progress toward the first objective revealed that overexpression of BCL-2 dramatically enhanced the activity of the androgen receptor (manuscript submitted). We also demonstrated that PS-341 displays strong activity against established human prostate cancer xenografts. Subsequent analysis of PS-34l's interactions with conventional chemotherapy demonstrated that it promotes the activities of DNA damaging agents but interferes with taxoids in a schedule-dependent fashion. Our data have been instrumental in helping NCI/CTEP design upcoming PS-341-based clinical trials.