Plenary Session 1: Translational Cancer Medicine
Sunday, April 18, 2010, 9:30 AM-12:15 PM
Presentation Title: Overcoming drug resistance: Lessons from prostate cancer
Charles L. Sawyers, M.D., is past president of the American Society of Clinical Investigation, has served on the National Cancer Institute's Board of Scientific Councilors, and is a member of the Institute of Medicine, National Academy of Sciences. In 2009, he was awarded the Lasker-Debakey Prize for Clinical Medical Research.
Recent Research
Androgen receptor (AR) transcriptional activity is crucial for the growth and survival of both hormone-sensitive and castration-resistant prostate cancer. Sawyers and colleagues show that AR transcriptional activity is blocked by histone deacetylase inhibitors in castration-resistant prostate cancer models, suggesting their use in the treatment of this lethal stage of the disease. (See "Detailed Research Summary" below.) They published an article on this topic in Cancer Research:
Detailed Research Summary
Current hormone therapies, such as androgen receptor (AR) antagonists, eventually fail, leading to a lethal castration-resistant stage of prostate cancer. Sawyers and colleagues have previously shown that the transition from castration-sensitive to castration-resistant disease is associated with the overexpression of AR protein. Agonists promote the recruitment of AR and coactivators that have histone acetyltransferase activity to promoters of AR target genes, leading to histone acetylase and active transcription of these genes. Antagonists promote the recruitment of corepressors that complex with histone deacetylases (HDACs) and repress gene expression.
In this Cancer Research article, Sawyers and colleagues examine the effect of HDAC inhibitors on AR function. They show that HDAC inhibitors, including SAHA (vorinostat) and LBH589, which are currently being tested in the clinic, decrease AR protein levels. Furthermore, HDAC inhibitors block AR transcriptional activity independent of AR protein levels, resulting in the inhibition of various AR-mediated genes, including the TMPRSS2 gene, involved in fusion with ETS family members in a majority of prostate cancers. These HDAC inhibitors are also able to inhibit AR activity in castration-resistant prostate cancer models. These data show that HDACs are required for AR transcriptional activity, suggesting the use of HDAC inhibitors in the treatment of castration-resistant prostate cancer.