Prostate cancer (PCa) is the leading cancer in the U.S. population and the second leading cause of cancer death in men. Therapy for locally advanced disease remains contentious and an increasing number of disparate options are available. Perhaps the most pressing issue in PCa management is the need to predict, at the time of diagnosis, which tumors will remain indolent and which will progress rapidly. The ability to fulfill that goal would eliminate the prostate-specific antigen (PSA)-mediated over detection and overtreatment of clinically insignificant disease. PCa tends to undergo definitive treatment despite the side effects of bowel, bladder and/or sexual dysfunction. The ability to predict the """"""""bad actors"""""""" among diagnosed tumors would provide rationale for expectant management, which may be appropriate and obviate serious morbidity, but is not widely embraced in this country. Currently treatment decisions are based on making a best guess at the biology of the tumor from as much indirect information as possible, i.e., PSA, digital rectal examination and biopsy. We believe that molecular imaging techniques, with their ability to interrogate receptor/enzyme/antigen/transporter concentrations and protein interaction networks, provide the best opportunity for understanding PCa biology upon diagnosis. Examples of the predictive capacity of molecular imaging techniques as applied to real clinical cases are becoming evident. More accurate staging would facilitate treatment decisions and lead to a better outcome for patients. Also in dire need is a way to detect small lesions, i.e., recurrent tumors in the surgical bed, local lymph node invasion and other subtle manifestations of the disease in men with an elevated PSA but no other obvious symptoms. The current standard of PCa staging is shifting. Metabolic imaging techniques such as magnetic resonance spectroscopy (MRS), positron emission tomography (PET) and single photon emission computed tomography (SPECT) are gaining favor over the anatomic techniques of computed tomography (CT) and MR, which merely detect enlarged tissue, revealing nothing of its underlying physiology. A major focus of our group is to devise new molecular imaging agents and techniques for imaging PCa. Our imaging target of choice to date has been the prostate-specific membrane antigen (PSMA), which is elevated in PCa, in particular androgen-independent disease, and is expressed in most solid tumor neovasculature. In fact PSMA is the target for one of the few mechanism-based molecular imaging agents for PCa, i.e., the radiolabeled monoclonal antibody (mAb) [111In]capromab pendetide (Cyt-356, ProstaScint). Other imaging agents for PCa are emerging, but each suffers from its unique problems such as lack of specificity and unknown mechanism of action. A promising new target for imaging PCa is the 1-methylacyl-coenzyme A racemase (AMACR). We and others identified this enzyme as a marker for PCa as it is significantly upregulated in the disease as compared to normal, surrounding prostate tissue. As such we believe that we can fashion substrates or inhibitors of AMACR into sensitive imaging agents for intraprostatic disease. However there are few known compounds that bind to AMACR. As an intracytoplasmic protein, and because of the inherently poor pharmacokinetics of antibodies for imaging, we cannot use our monoclonal antibodies to study AMACR in vivo. Instead we have chosen to develop a high-throughput technique to find suitable low molecular weight candidates for imaging AMACR.
Badly needed are markers that can identify minimal disease in prostate cancer, within the gland itself as well as within metastases, which might also be able to predict the biological behavior of tumors detected - will they lie dormant or will they disseminate? We have identified 1-methylacyl-coenzyme A racemase (AMACR) to be a marker that is significantly upregulated in prostate cancer compared to surrounding, normal prostate tissue. In this project we will develop a high-throughput screen to identify compounds that bind strongly to AMACR, which we can subsequently derivatize for high-sensitivity prostate cancer imaging.
|Wilson, Brice A P; Wang, Haofan; Nacev, Benjamin A et al. (2011) High-throughput screen identifies novel inhibitors of cancer biomarker ýý-methylacyl coenzyme A racemase (AMACR/P504S). Mol Cancer Ther 10:825-38|