Editor's Commentary - Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen

BERKELEY, CA (UroToday.com) - In the online edition of the Proceedings of the National Academy of Sciences, Dr. Charles Sawyers and his research team report on a new imaging reagent to map androgen receptor (AR) signaling and AR activity in men with castration-resistant prostate cancer (CRPC).

They hypothesized that differential sensitivity of distinct metastatic lesions to anti-androgens may be explained by different degrees of AR inhibition, which might be overcome using a radiopharmaceutical agent that measures intratumoral AR signaling. The focus was on prostate-specific membrane antigen (PSMA), which in one report was repressed by androgen in a prostate cancer cell line. The investigators expanded this observation to other AR-positive prostate cancer cell lines.

Next they confirmed that AR was required for the androgen repression of PSMA. They did this by ablating AR with siRNA or the next generation anti-androgen MDV3100 and finding increased expression of PSMA. They needed to translate the degree of PSMA repression to mouse xenografts models to determine if it was sufficient for quantitative imaging using PET scanning. Mice with prostate tumors were imaged by PET using 64Cu-J591, then underwent either no treatment or treatment with testosterone or DHT for 6 days. Repeat imaging showed little PET variation in the untreated group, but greatly reduced incorporation of 64Cu-J591 in tumors treated with testosterone or DHT. 64Cu-J591 uptake was also shown to be unaffected in androgen-insensitive host tissues, supporting the hypothesis of specificity for testosterone and DHT. Intact mice grew AR-bearing tumors and underwent 64Cu-J591 imaging. They then received placebo, castration or MDV3100 and were reimaged after 6 days. The castration and MDV3100 groups had significantly increased incorporation of 64Cu-J591 compared to controls. This technology may prove useful in patients with CRPC.

 

Evans MJ, Smith-Jones PM, Wongvipat J, Navarro V, Kim S, Bander NH, Larson SM, Sawyers CL

 

 

Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9578-82
10.1073/pnas.1106383108

PubMed Abstract
PMID: 21606347

UroToday.com Prostate Cancer Section

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