PET and Evaluation of Androgen Receptor Role in prostate cancer. Determination of AR level of occupancy in prostate cancer by PET imaging will permit tailored targeted therapy. This will allow a personalized medicine approach in one of the major world health problems.

The androgen receptor (AR) is a member of the steroid/thyroid hormone receptor super-family that plays a critical role in the development and maintenance of male secondary sexual phenotype.  It is a cellular regulatory protein that, following androgen binding, migrates into the nucleus, binds to specific DNA sequences called androgen response elements, and modulates the transcription of target genes. The AR is also believed to be involved in prostate carcinogenesis, and amplification of AR is present in most advanced prostate cancer specimens.

Prostate cancer is estimated to represent 30% of new cancer cases in U.S. males. Approximately 80-90% of prostate cancers are dependent on androgen activity at initial diagnosis, and endocrine therapy of prostate cancer is directed toward the reduction of serum androgens and inhibition of AR. On the other hand, some very aggressive forms of prostate cancer were shown to have lost the expression of AR, and are insensitive to inhibition of the AR. Antiandrogens are used to counteract the undesirable actions of excessive androgens.

Nonsteroidal antiandrogens, such as flutamide, nilutamide, and bicalutamide, were shown to bind exclusively to the AR and are successfully used in the clinic for the treatment of AR-dependent prostate cancer. Since the AR is a specific target for prostate cancer treatment and since loss of expression of AR have been observed in several aggressive tumors, it is critical to determine the role of AR in individual patients in order to guide and monitor  treatment. To date, imaging tools, including Positron Emission Tomography (PET) for diagnosing local recurrence and metastatic sites of prostate cancer are sub-optimal.

We have pioneered the development of novel 18F-labeled nonsteroidial antiandrogen compounds, 18F-labeled flutamide derivatives, as potential PET biomarker for prostate cancer. In vitro analysis of these bioprobes showed their potential as PET tracers for in vivo investigation of prostate cancer. We will continue the research project with these labeled compounds and other novel labeled biomarkers by performing in vivo studies and a Micro-PET imaging and data analysis in tumor bearing animal models. This will permit the identification of the best PET tracer, the evaluation of drug potency, and the correlation of treatment response with AR occupancy.