BERKELEY, CA (UroToday.com) - In a case described in our recently published paper, we were faced with choosing the best treatment for a patient with prostate cancer who had progressed through radical prostatectomy, radiation therapy, several rounds of surgical debulking of pelvic recurrent disease, hormonal therapy, taxotere and doxorubicin. In the not too distant past, the assumption would have been that this cancer’s growth was independent of testosterone and further hormonal therapy would be viewed as offering little benefit.
We now understand that a majority of prostate cancers still depend on the action of the androgen receptor for growth and survival. In some cases, resistance develops because of marked overexpression of the androgen receptor. As an alternate, protein phosphorylation can allow the androgen receptor to translocate to the nucleus in the absence of androgen. Additionally, prostate cancer cells have also been shown to produce sufficient androgen to support cancer progression. These observations have led to the development of new drugs designed to overcome these resistance mechanisms. Abiraterone effectively blocks prostate cancer cell androgen synthesis. MDV3100 appears to be much more effective than previously available androgen receptor antagonists. Dasatinib has been shown to block tyrosine phosphorylation of the androgen receptor, blocking androgen independent receptor activation. Following two promising Phase II trials, a Phase III trial testing taxotere alone versus taxotere plus dasatinib was conducted and the results are likely to be released this fall.
Each of these mechanisms requires the presence of the androgen receptor, so the absence of that receptor would appear to rule out a response to any of these approaches. This is the approach we took in analyzing this patient’s treatment options. Molecular profiling revealed that not only was androgen receptor present, but it was significantly overexpressed. At the time this information became available, Zytiga was FDA-approved but not yet available. As a result, we chose to base treatment on ketoconazole and estradiol. The result was near complete resolution of his disease. This result leads us to propose the hypothesis that testing androgen receptor expression will allow identification of patients most likely to respond to these new drugs, as well as older drugs like ketoconazole.
Written by:
Charles E. Myers, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Foundation for Cancer Research and Education, Earlysville, Charlottesville, VA USA, and
Foundation for Cancer Research and Education, 690 Bent Oaks Drive, Earlysville, VA USA
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