European Radiology

, Volume 25, Issue 5, pp 1294–1302 | Cite as

Molecular imaging of prostate cancer: translating molecular biology approaches into the clinical realm

  • Hebert Alberto Vargas
  • Jan Grimm
  • Olivio F. Donati
  • Evis Sala
  • Hedvig Hricak


The epidemiology of prostate cancer has dramatically changed since the introduction of prostate-specific antigen (PSA) screening in the 1980’s. Most prostate cancers today are detected at early stages of the disease and are considered ‘indolent’; however, some patients’ prostate cancers demonstrate a more aggressive behaviour which leads to rapid progression and death. Increasing understanding of the biology underlying the heterogeneity that characterises this disease has led to a continuously evolving role of imaging in the management of prostate cancer. Functional and metabolic imaging techniques are gaining importance as the impact on the therapeutic paradigm has shifted from structural tumour detection alone to distinguishing patients with indolent tumours that can be managed conservatively (e.g., by active surveillance) from patients with more aggressive tumours that may require definitive treatment with surgery or radiation. In this review, we discuss advanced imaging techniques that allow direct visualisation of molecular interactions relevant to prostate cancer and their potential for translation to the clinical setting in the near future. The potential use of imaging to follow molecular events during drug therapy as well as the use of imaging agents for therapeutic purposes will also be discussed.

Key Points

• Advanced imaging techniques allow direct visualisation of molecular interactions in prostate cancer.

• MRI/PET, optical and Cerenkov imaging facilitate the translation of molecular biology.

• Multiple compounds targeting PSMA expression are currently undergoing clinical translation.

• Other targets (e.g., PSA, prostate-stem cell antigen, GRPR) are in development.


Prostate cancer Molecular imaging MRI/PET Optical imaging Cerenkov imaging 



Magnetic resonance imaging


Positron-emission tomography


Single-photon emission computed tomography


Prostate-specific membrane antigen


Prostate-specific antigen


Prostate stem cell antigen


Gastrin-releasing peptide receptor


Benign prostatic hyperplasia



The scientific guarantor of this publication is Hedvig Hricak. The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. The authors state that this work has not received any funding. No complex statistical methods were necessary for this paper. Institutional Review Board approval was not required because this was a review article.


  1. 1.
    Elias DR, Thorek DLJ, Chen AK, Czupryna J, Tsourkas A (2008) In vivo imaging of cancer biomarkers using activatable molecular probes. Cancer Biomarkers 4:287–305PubMedGoogle Scholar
  2. 2.
    Thorek DL, Grimm J (2012) Enzymatically activatable diagnostic probes. Curr Pharm Biotechnol 13:523–536CrossRefPubMedGoogle Scholar
  3. 3.
    Ruggiero A, Holland JP, Lewis JS, Grimm J (2010) Cerenkov luminescence imaging of medical isotopes. J Nucl Med 51:1123–1130CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Huggins C, Hodges CV (2002) Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol 168:9–12CrossRefPubMedGoogle Scholar
  5. 5.
    Azzouni F, Mohler J (2012) Biology of castration-recurrent prostate cancer. Urol Clin N Am 39:435–452CrossRefGoogle Scholar
  6. 6.
    Scher HI, Beer TM, Higano CS et al (2010) Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 375:1437–1446CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Larson SM, Morris M, Gunther I et al (2004) Tumor localization of 16beta-18 F-fluoro-5alpha-dihydrotestosterone versus 18 F-FDG in patients with progressive, metastatic prostate cancer. J Nucl Med 45:366–373PubMedGoogle Scholar
  8. 8.
    Beattie BJ, Smith-Jones PM, Jhanwar YS et al (2010) Pharmacokinetic assessment of the uptake of 16beta-18 F-fluoro-5alpha-dihydrotestosterone (FDHT) in prostate tumors as measured by PET. J Nucl Med 51:183–192CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Zanzonico PB, Finn R, Pentlow KS et al (2004) PET-based radiation dosimetry in man of 18 F-fluorodihydrotestosterone, a new radiotracer for imaging prostate cancer. J Nucl Med 45:1966–1971PubMedGoogle Scholar
  10. 10.
    Fox JJ, Autran-Blanc E, Morris MJ et al (2011) Practical approach for comparative analysis of multilesion molecular imaging using a semiautomated program for PET/CT. J Nucl Med 52:1727–1732CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Vargas HA, Wassberg C, Fox JJ et al (2014) Bone metastases in castration-resistant prostate cancer: associations between morphologic CT patterns, glycolytic activity, and androgen receptor expression on PET and overall survival. Radiology 271:220–229CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Su SL, Huang IP, Fair WR, Powell CT, Heston WDW (1995) Alternatively spliced variants of prostate-specific membrane antigen Rna - ratio of expression as a potential measurement of progression. Cancer Res 55:1441–1443PubMedGoogle Scholar
  13. 13.
    Mannweiler S, Amersdorfer P, Trajanoski S, Terrett JA, King D, Mehes G (2009) Heterogeneity of prostate-specific membrane antigen (PSMA) expression in prostate carcinoma with distant metastasis. Pathol Oncol Res 15:167–172CrossRefPubMedGoogle Scholar
  14. 14.
    Minner S, Wittmer C, Graefen M et al (2011) High level PSMA expression is associated with early PSA recurrence in surgically treated prostate cancer. Prostate 71:281–288CrossRefPubMedGoogle Scholar
  15. 15.
    Chikkaveeraiah BV, Bhirde A, Malhotra R, Patel V, Gutkind JS, Rusling JF (2009) Single-wall carbon nanotube forest arrays for immunoelectrochemical measurement of four protein biomarkers for prostate cancer. Anal Chem 81:9129–9134CrossRefPubMedGoogle Scholar
  16. 16.
    Lapidus RG, Tiffany CW, Isaacs JT, Slusher BS (2000) Prostate-specific membrane antigen (PSMA) enzyme activity is elevated in prostate cancer cells. Prostate 45:350–354CrossRefPubMedGoogle Scholar
  17. 17.
    Chen Y, Dhara S, Banerjee SR et al (2009) A low molecular weight PSMA-based fluorescent imaging agent for cancer. Biochem Biophys Res Commun 390:624–629CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Hillier SM, Maresca KP, Femia FJ et al (2009) Preclinical evaluation of novel glutamate-urea-lysine analogues that target prostate-specific membrane antigen as molecular imaging pharmaceuticals for prostate cancer. Cancer Res 69:6932–6940CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Haseman MK, Reed NL, Rosenthal SA (1996) Monoclonal antibody imaging of occult prostate cancer in patients with elevated prostate-specific antigen. Positron emission tomography and biopsy correlation. Clin Nucl Med 21:704–713CrossRefPubMedGoogle Scholar
  20. 20.
    Babaian RJ, Sayer J, Podoloff DA, Steelhammer LC, Bhadkamkar VA, Gulfo JV (1994) Radioimmunoscintigraphy of pelvic lymph nodes with 111indium-labeled monoclonal antibody CYT-356. J Urol 152:1952–1955PubMedGoogle Scholar
  21. 21.
    Polascik TJ, Manyak MJ, Haseman MK et al (1999) Comparison of clinical staging algorithms and 111indium-capromab pendetide immunoscintigraphy in the prediction of lymph node involvement in high risk prostate carcinoma patients. Cancer 85:1586–1592CrossRefPubMedGoogle Scholar
  22. 22.
    Elgamal AA, Holmes EH, Su SL et al (2000) Prostate-specific membrane antigen (PSMA): current benefits and future value. Semin Surg Oncol 18:10–16CrossRefPubMedGoogle Scholar
  23. 23.
    Holland JP, Divilov V, Bander NH, Smith-Jones PM, Larson SM, Lewis JS (2010) 89Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo. J Nucl Med 51:1293–1300CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Ruggiero A, Holland JP, Hudolin T et al (2011) Targeting the internal epitope of prostate-specific membrane antigen with 89Zr-7E11 immuno-PET. J Nucl Med 52:1608–1615CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Holland JP, Caldas-Lopes E, Divilov V et al (2010) Measuring the pharmacodynamic effects of a novel Hsp90 inhibitor on HER2/neu expression in mice using Zr-DFO-trastuzumab. PLoS One 5:e8859CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Liu H, Moy P, Kim S et al (1997) Monoclonal antibodies to the extracellular domain of prostate-specific membrane antigen also react with tumor vascular endothelium. Cancer Res 57:3629–3634PubMedGoogle Scholar
  27. 27.
    Thorek D, Robertson R, Bacchus WA et al (2012) Cerenkov imaging - a new modality for molecular imaging. Am J Nucl Med Mol Imaging 2:163–173PubMedCentralPubMedGoogle Scholar
  28. 28.
    Wright GL Jr, Grob BM, Haley C et al (1996) Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy. Urology 48:326–334CrossRefPubMedGoogle Scholar
  29. 29.
    Evans MJ, Smith-Jones PM, Wongvipat J et al (2011) Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen. Proc Natl Acad Sci U S A 108:9578–9582CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Barinka C, Rovenska M, Mlcochova P et al (2007) Structural insight into the pharmacophore pocket of human glutamate carboxypeptidase II. J Med Chem 50:3267–3273CrossRefPubMedGoogle Scholar
  31. 31.
    Mease RC, Dusich CL, Foss CA et al (2008) N-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl]-4-[18 F]fluorobenzyl-L-cysteine, [18 F]DCFBC: a new imaging probe for prostate cancer. Clin Cancer Res 14:3036–3043CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Cho SY, Gage KL, Mease RC et al (2012) Biodistribution, tumor detection, and radiation dosimetry of 18 F-DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer. J Nucl Med 53:1883–1891CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Barrett JA, Coleman RE, Goldsmith SJ et al (2013) First-in-man evaluation of 2 high-affinity PSMA-avid small molecules for imaging prostate cancer. J Nucl Med 54:380–387CrossRefPubMedGoogle Scholar
  34. 34.
    Chen Z, Penet MF, Nimmagadda S et al (2012) PSMA-targeted theranostic nanoplex for prostate cancer therapy. ACS Nano 6:7752–7762CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Grimm J, Scheinberg DA (2011) Will nanotechnology influence targeted cancer therapy? Semin Radiat Oncol 21:80–87CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Nakajima T, Mitsunaga M, Bander NH, Heston WD, Choyke PL, Kobayashi H (2011) Targeted, activatable, in vivo fluorescence imaging of prostate-specific membrane antigen (PSMA) positive tumors using the quenched humanized J591 antibody-indocyanine green (ICG) conjugate. Bioconjug Chem 22:1700–1705CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Liu T, Wu LY, Hopkins MR, Choi JK, Berkman CE (2010) A targeted low molecular weight near-infrared fluorescent probe for prostate cancer. Bioorg Med Chem Lett 20:7124–7126CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Grimm J, Kirsch DG, Windsor SD et al (2005) Use of gene expression profiling to direct in vivo molecular imaging of lung cancer. Proc Natl Acad Sci U S A 102:14404–14409CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    van Dam GM, Themelis G, Crane LM et al (2011) Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-alpha targeting: first in-human results. Nat Med 17:1315–1319CrossRefPubMedGoogle Scholar
  40. 40.
    Schaafsma BE, Mieog JS, Hutteman M et al (2011) The clinical use of indocyanine green as a near-infrared fluorescent contrast agent for image-guided oncologic surgery. J Surg Oncol 104:323–332CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Schaafsma BE, van der Vorst JR, Gaarenstroom KN et al (2012) Randomized comparison of near-infrared fluorescence lymphatic tracers for sentinel lymph node mapping of cervical cancer. Gynecol Oncol 127:126–130CrossRefPubMedCentralPubMedGoogle Scholar
  42. 42.
    Song KM, Lee S, Ban C (2012) Aptamers and their biological applications. Sensors (Basel) 12:612–631CrossRefGoogle Scholar
  43. 43.
    Lupold SE, Hicke BJ, Lin Y, Coffey DS (2002) Identification and characterization of nuclease-stabilized RNA molecules that bind human prostate cancer cells via the prostate-specific membrane antigen. Cancer Res 62:4029–4033PubMedGoogle Scholar
  44. 44.
    Farokhzad OC, Cheng J, Teply BA et al (2006) Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci U S A 103:6315–6320CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Chu TC, Marks JW 3rd, Lavery LA et al (2006) Aptamer:toxin conjugates that specifically target prostate tumor cells. Cancer Res 66:5989–5992CrossRefPubMedGoogle Scholar
  46. 46.
    Tong R, Coyle VJ, Tang L, Barger AM, Fan TM, Cheng J (2010) Polylactide nanoparticles containing stably incorporated cyanine dyes for in vitro and in vivo imaging applications. Microsc Res Tech 73:901–909CrossRefPubMedGoogle Scholar
  47. 47.
    Yu MK, Kim D, Lee IH, So JS, Jeong YY, Jon S (2011) Image-guided prostate cancer therapy using aptamer-functionalized thermally cross-linked superparamagnetic iron oxide nanoparticles. Small 7:2241–2249CrossRefPubMedGoogle Scholar
  48. 48.
    Rockey WM, Huang L, Kloepping KC, Baumhover NJ, Giangrande PH, Schultz MK (2011) Synthesis and radiolabeling of chelator-RNA aptamer bioconjugates with copper-64 for targeted molecular imaging. Bioorg Med Chem 19:4080–4090CrossRefPubMedCentralPubMedGoogle Scholar
  49. 49.
    Thompson IM, Pauler DK, Goodman PJ et al (2004) Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med 350:2239–2246CrossRefPubMedGoogle Scholar
  50. 50.
    Lilja H, Ulmert D, Vickers AJ (2008) Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nat Rev Cancer 8:268–278CrossRefPubMedGoogle Scholar
  51. 51.
    Ulmert D, Evans MJ, Holland JP et al (2012) Imaging androgen receptor signaling with a radiotracer targeting free prostate-specific antigen. Cancer Discov 2:320–327CrossRefPubMedCentralPubMedGoogle Scholar
  52. 52.
    Stege RH, Tribukait B, Carlstrom KAM, Grande M, Pousette AHL (1999) Tissue PSA from fine-needle biopsies of prostatic carcinoma as related to serum PSA, clinical stage, cytological grade, and DNA ploidy. Prostate 38:183–188CrossRefPubMedGoogle Scholar
  53. 53.
    Lilja H (1985) A kallikrein-like serine protease in prostatic fluid cleaves the predominant seminal vesicle protein. J Clin Invest 76:1899–1903CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    Lepin EJ, Leyton JV, Zhou Y et al (2010) An affinity matured minibody for PET imaging of prostate stem cell antigen (PSCA)-expressing tumors. Eur J Nucl Med Mol Imaging 37:1529–1538CrossRefPubMedCentralPubMedGoogle Scholar
  55. 55.
    Ren J, Wang F, Wei G et al (2012) MRl of prostate cancer antigen expression for diagnosis and immunotherapy. PLoS One 7:e38350CrossRefPubMedCentralPubMedGoogle Scholar
  56. 56.
    Gao X, Luo Y, Wang Y et al (2012) Prostate stem cell antigen-targeted nanoparticles with dual functional properties: in vivo imaging and cancer chemotherapy. Int J Nanomedicine 7:4037–4051CrossRefPubMedCentralPubMedGoogle Scholar
  57. 57.
    Smith CJ (2003) Radiochemical investigations of gastrin-releasing peptide receptor-specific [(99 m)Tc(X)(CO)3-Dpr-Ser-Ser-Ser-Gln-Trp-Ala-Val-Gly-His-Leu-Met-(NH2)] in PC-3, tumor-bearing, rodent models: syntheses, radiolabeling, and in vitro/in vivo studies where Dpr = 2,3-diaminopropionic acid and X = H2O or P(CH2OH)3. Cancer Res (Baltimore) 63:4082–4088Google Scholar
  58. 58.
    De Vincentis G, Remediani S, Varvarigou AD et al (2004) Role of 99mTc-bombesin scan in diagnosis and staging of prostate cancer. Cancer Biother Radiopharm 19:81–84CrossRefPubMedGoogle Scholar
  59. 59.
    Scopinaro F, De Vincentis G, Varvarigou AD et al (2003) 99mTc-bombesin detects prostate cancer and invasion of pelvic lymph nodes. Eur J Nucl Med Mol Imaging 30:1378–1382CrossRefPubMedGoogle Scholar
  60. 60.
    Honer M, Mu L, Stellfeld T et al (2011) 18 F-labeled bombesin analog for specific and effective targeting of prostate tumors expressing gastrin-releasing peptide receptors. J Nucl Med 52:270–278CrossRefPubMedGoogle Scholar
  61. 61.
    Cai QY, Yu P, Besch-Williford C et al (2012) Near-infrared fluorescence imaging of gastrin releasing peptide receptor targeting in prostate cancer lymph node metastases. Prostate. doi: 10.1002/pros.22630:n-a-n/a PubMedGoogle Scholar

Copyright information

© European Society of Radiology 2015

Authors and Affiliations

  • Hebert Alberto Vargas
    • 1
  • Jan Grimm
    • 1
    • 2
  • Olivio F. Donati
    • 1
    • 3
  • Evis Sala
    • 1
  • Hedvig Hricak
    • 1
  1. 1.Department of RadiologyMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer CenterNew YorkUSA
  3. 3.Institute of Diagnostic and Interventional RadiologyUniversity Hospital ZurichZurichSwitzerland

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