Repression of the Androgen Receptor by WT1, a Tumor Suppressor Gene.
Abstract
No effective therapy currently exists for androgen-independent, metastatic prostate cancer. Using an orthotopic animal model, we isolated androgen-sensitive and androgen-insensitive variants of the human LNCaP prostate cancer cell line. The latter display increased levels of BCL-2 and resistance to multiple triggers for apoptosis. Progress over the past year has demonstrated that the increased BCL-2 is linked to increased ligand-independent androgen receptor activity and increased serum-dependent activity of the transcription factor, NFkB. Parallel studies have evaluated the in vivo efficacy and toxicity of a novel drug, PS-341 (a proteasome inhibitor), that is capable of bypassing BCL-2-mediated resistance in vitro. The drug promoted extensive apoptosis in established orthotopic human PC-3 prostate tumors. Analysis of the mechanisms involved revealed direct effects on tumor cells as well as indirect effects on tumor vasculature. Future efforts will be directed at further dissecting the transcriptional control of apoptosis resistance in the androgen-independent prostate cancer cells. Further preclinical studies with PS-341 will include evaluating its effects on p53-positive (LNCaP-Pro5) orthotopic tumors and in combination with other chemotherapeutic agents.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 1999
- Accession Number
- ADA376125
Entities
People
- David J. Mcconkey
Organizations
- The University of Texas MD Anderson Cancer Center