) The incidence of prostate cancer is increasing annually and, in 1997, it is expected that 41,900 men will die from prostate cancer. Initially, the majority of men with prostate cancer can be treated successfully by removing testosterone from the system. However, after a median of 18 months, the disease becomes androgen independent and starts to regrow in the absence of testosterone. A long term objective of this project is to study the molecular mechanisms of androgen independence. The focus of this project will be on the androgen receptor. The androgen receptor regulates growth in normal prostate cells and in prostate cancer. In prostate cancer, mutations in the androgen receptor have been found in androgen independent prostate cancer but are rare in early stage hormone sensitive cancer. Functional studies of mutant androgen receptors have shown that mutant receptors have different binding affinities and specificities for hormones and hormone antagonists. In particular, the prostate cancer antagonist hydroxyflutamide actually stimulates some mutant receptors. In addition, it has been observed that some patients will have a clinical response to discontinuation of antiandrogen therapy. It is important, therefore, to examine the prevalence and type of androgen receptor mutations and identify their importance in the natural history of prostate cancer.
The first aim of this project is to evaluate the frequency and type of androgen receptor mutations in tumors from patents with advanced androgen independent prostate cancer. Prostate tumor sample will be obtained from bone marrow biopsies of patients enrolling on a Cancer and Leukemia Group B trial designed to study the withdrawal of antiandrogen alone or the withdrawal of antiandrogen combined with adrenal hormone blockade. This trial will provide 230 bone marrow samples from which tumor may be obtained to examine the sequence the androgen receptor. An additional 120 bone marrow samples will be obtained during the second year from patients enrolling on a successor trial of secondary oral antiandrogen therapy.
The second aim of this project is to evaluate the association between receptor mutations and clinical outcomes, including survival and response to antiandrogen withdrawal and response to secondary oral antiandrogen therapy. It is hoped that an understanding of molecular changes in the androgen receptor with clinical correlation may provide insight into the progression of androgen independence and lead to more durable hormonal therapies.
| Ross, Robert W; Halabi, Susan; Ou, San-San et al. (2005) Predictors of prostate cancer tissue acquisition by an undirected core bone marrow biopsy in metastatic castration-resistant prostate cancer--a Cancer and Leukemia Group B study. Clin Cancer Res 11:8109-13 |
| Taplin, Mary-Ellen; Rajeshkumar, Barur; Halabi, Susan et al. (2003) Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663. J Clin Oncol 21:2673-8 |
| Taplin, M E; Bubley, G J; Ko, Y J et al. (1999) Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res 59:2511-5 |
