Molecular Imaging of Prostate Cancer Background: Prostate cancer is the 2nd leading cause of cancer death in males. As a result of screening with serum prostate specific antigen (PSA) there has been a dramatic increase in the number of men diagnosed with prostate cancer, about 220,000 new diagnoses annually. The diagnosis is being made at a younger age yet the morbidity of the standard treatments; surgery and radiation---remain unchanged. Thus, men with the diagnosis of prostate cancer are likely being overtreated for their disease and will live with the consequences of this treatment for many years greatly affecting the Quality of Life Years (QALY). The ultimate answer to this dilemma is serum biomarkers that identify lethal cancers but not incidental cancers but this is unlikely to occur soon. In the meantime, methods of localizing prostate cancer and treating them with minimally invasive therapy would dramatically lessen the morbidity associated with widespread screening and the overdiagnosis of prostate cancer. A variety of imaging methods have been developed and we are exploring their role in localizing early prostate cancer(1). The Urologic Oncology Branch is partnering with the MIP to develop new imaging methods to be coupled with their minimally invasive treatment methods which include RF ablation, cryotherapy and alcohol ablation. Pre-Clinical Research The MIP has been investigating a variety of targets in conjunction with Mike Buck in the Laboratory of Pathology. We have evaluated an antibody against PSMA (3TC) in animal models of prostate cancer and while this agent was successful in targeting LnCAP and PC3 tumor lines, the agent competes against many similar agents further along in clinical development. A novel marker of prostate cancer, epithelial cell adhesion molecule (EpCAM) has been identified as a stromal target by the Buck lab. Unlike conventional prostate cancer targets, this target is located in the stroma associated with cancers. As a result it may be more accessible than prostate cancer cell markers that are within acini and located behind the basement membrane (although the basement membrane is often disrupted in prostate cancer). Stroma is part of the microvenvironment that includes vessels and lymphatics and therefore may be more """"""""targetable"""""""" . A human antibody against EpCAM has been developed and is in clinical trials. The radiolabeled antibody has been tested in human tissue. Analagous markers have been found in the canine model of prostate cancer and trials in dogs are being designed. Clinical Trials The MIP has been studying prostate cancer imaging in humans since its inception. We perform endorectal coil MRI at 3T which includes DCE-MRI, MR Spectroscopy and Diffusion Weighted Imaging. We have developed analytic tools for all three techniques in conjunction with a CRADA with the Philips Medical Systems. We have demonstrated that DCE-MRI improves the specificity of 3T MRI for prostate cancer. However, there remain significant limitations in the sensitivity and specificity of 3T MRI. After patients undergo prostatectomy and their specimens are available for review it is clear that less than 40% would be amenable for focal therapy based on being single, well circumscribed lesions that are visible on MRI. We have designed MR guided biopsy devices in conjunction with Johns Hopkins University School of Bioengineering but concluded that this device was too complex and time consuming for clinical use(2-5). This device was used to define treatment fields for High Dose Rate Brachytherapy, however, it proved somewhat cumbersome. Therefore, working with Philips Medical Systems we have designed an US-MR fusion system that takes the data from the 3T MRI and fuses it to the real time ultrasound image(6). Biopsy and interventional procedures can then be performed under """"""""MR guidance"""""""" using the ultrasound. This device has been used successfully in 25 patients. We will shortly perform a study in dogs in which the accuracy of needle placement is confirmed. We believe that MRI is fundamentally limited in identifying intraprostatic disease. We are conducting a PET study using 11C-Acetate to study the value of this agent in identifying intraprostatic lesions(1). Patients will also undergo 3T MRI and the PET image will be fused to the MRI. We have plans to study 18F-ACBC an agent associated with amino acid transport which has shown benefit in localizing prostate cancer. Ultimately we wish to combine PET-MR studies and conduct minimally invasive therapies after US fusion. 1. Hricak, H., Choyke, P. L., Eberhardt, S. C., Leibel, S. A., and Scardino, P. T. Imaging prostate cancer: a multidisciplinary perspective. Radiology, 243: 28-53, 2007. 2. Susil, R. C., Menard, C., Krieger, A., Coleman, J. A., Camphausen, K., Choyke, P., Fichtinger, G., Whitcomb, L. L., Coleman, C. N., and Atalar, E. Transrectal prostate biopsy and fiducial marker placement in a standard 1.5T magnetic resonance imaging scanner. J Urol, 175: 113-120, 2006. 3. Menard, C., Susil, R. C., Choyke, P., Coleman, J., Grubb, R., Gharib, A., Krieger, A., Guion, P., Thomasson, D., Ullman, K., Gupta, S., Espina, V., Liotta, L., Petricoin, E., Fitchtinger, G., Whitcomb, L. L., Atalar, E., Coleman, C. N., and Camphausen, K. An interventional magnetic resonance imaging technique for the molecular characterization of intraprostatic dynamic contrast enhancement. Mol Imaging, 4: 63-66, 2005. 4. Susil, R. C., Camphausen, K., Choyke, P., McVeigh, E. R., Gustafson, G. S., Ning, H., Miller, R. W., Atalar, E., Coleman, C. N., and Menard, C. System for prostate brachytherapy and biopsy in a standard 1.5 T MRI scanner. Magn Reson Med, 52: 683-687, 2004. 5. Menard, C., Susil, R. C., Choyke, P., Gustafson, G. S., Kammerer, W., Ning, H., Miller, R. W., Ullman, K. L., Sears Crouse, N., Smith, S., Lessard, E., Pouliot, J., Wright, V., McVeigh, E., Coleman, C. N., and Camphausen, K. MRI-guided HDR prostate brachytherapy in standard 1.5T scanner. Int J Radiat Oncol Biol Phys, 59: 1414-1423, 2004. 6. Lattouf, J. B., Grubb, R. L., 3rd, Lee, S. J., Bjurlin, M. A., Albert, P., Singh, A. K., Ocak, I., Choyke, P., and Coleman, J. A. Magnetic resonance imaging-directed transrectal ultrasonography-guided biopsies in patients at risk of prostate cancer. BJU Int, 99: 1041-1046, 2007.
