Positron emission tomography (PET) imaging of prostate cancer with a gastrin releasing peptide receptor antagonist--from mice to men

Gesche Wieser, Rosalba Mansi, Anca L Grosu, Wolfgang Schultze-Seemann, Rebecca A Dumont-Walter, Philipp T Meyer, Helmut R Maecke, Jean Claude Reubi, Wolfgang A Weber, Gesche Wieser, Rosalba Mansi, Anca L Grosu, Wolfgang Schultze-Seemann, Rebecca A Dumont-Walter, Philipp T Meyer, Helmut R Maecke, Jean Claude Reubi, Wolfgang A Weber

Abstract

Ex vivo studies have shown that the gastrin releasing peptide receptor (GRPr) is overexpressed on almost all primary prostate cancers, making it a promising target for prostate cancer imaging and targeted radiotherapy.

Methods: Biodistribution, dosimetry and tumor uptake of the GRPr antagonist ⁶⁴Cu-CB-TE2A-AR06 [(⁶⁴Cu-4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane)-PEG₄-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-LeuNH₂] were studied by PET/CT in four patients with newly diagnosed prostate cancer (T1c-T2b, Gleason 6-7).

Results: No adverse events were observed after injection of ⁶⁴Cu-CB-TE2A-AR06. Three of four tumors were visualized with high contrast [tumor-to-prostate ratio > 4 at 4 hours (h) post injection (p.i.)], one small tumor (T1c, < 5% tumor on biopsy specimens) showed moderate contrast (tumor-to-prostate ratio at 4 h: 1.9). Radioactivity was cleared by the kidneys and only the pancreas demonstrated significant accumulation of radioactivity, which rapidly decreased over time.

Conclusion: ⁶⁴Cu-CB-TE2A-AR06 shows very favorable characteristics for imaging prostate cancer. Future studies evaluating ⁶⁴Cu-CB-TE2A-AR06 PET/CT for prostate cancer detection, staging, active surveillance, and radiation treatment planning are necessary.

Keywords: Gastrin releasing peptide receptor; PET/CT; bombesin; prostate cancer..

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Chemical structure of 64Cu-CB-TE2A-AR06.
Figure 2
Figure 2
64Cu-CB-TE2A-AR06 PET/CT study of patient 2. Images were acquired 4 h p.i.. A, B: Coronal sections of PET and fused PET/CT. C: Axial PET/CT fusion images at the levels indicated by dotted lines in A. There is intense uptake by the prostate tumor (red arrows) and the pancreas. Kidneys, liver and intestines show only low tracer uptake. The PET images are scaled to an SUV of 5 (color bar).
Figure 3
Figure 3
Correlation between in vivo PET and ex vivo autoradiography. A, B: Transaxial fused PET/CT and PET 4 h p.i.. C: Ex vivo GRP receptor autoradiography demonstrating GRPr expression by the tumor.
Figure 4
Figure 4
A: Radioactivity concentration in the blood over time (mean and standard deviation) and bi-exponential fit of the data. The initial half-life of 64Cu-CB-TE2A-AR06 is 5 minutes and the terminal half-life 165 minutes. B: Radioactivity concentration in the tumors over time.
Figure 5
Figure 5
Tumor-to-normal-organ ratios over time.

References

    1. Hricak H, Choyke PL, Eberhardt SC, Leibel SA, Scardino PT. Imaging prostate cancer: a multidisciplinary perspective. Radiology. 2007;243:28–53.
    1. Picchio M, Briganti A, Fanti S. et al. The role of choline positron emission tomography/computed tomography in the management of patients with prostate-specific antigen progression after radical treatment of prostate cancer. Eur Urol. 2011;59:51–60.
    1. Souvatzoglou M, Weirich G, Schwarzenboeck S. et al. The sensitivity of [11C]choline PET/CT to localize prostate cancer depends on the tumor configuration. Clin Cancer Res. 2011;17:3751–3759.
    1. Jensen RT, Battey JF, Spindel ER, Benya RV. International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacol Rev. 2008;60:1–42.
    1. Markwalder R, Reubi JC. Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. Cancer Res. 1999;59:1152–1159.
    1. Bodei L, Ferrari M, Nunn A. et al. 177Lu-AMBA Bombesin analogue in hormone refractory prostate cancer patients: a phase I escalation study with single-cycle administrations [abstract] Eur J Nucl Med Mol Imaging. 2007;34(Suppl 2):S221.
    1. Schwartsmann G, DiLeone LP, Horowitz M. et al. A phase I trial of the bombesin/gastrin-releasing peptide (BN/GRP) antagonist RC3095 in patients with advanced solid malignancies. Invest New Drugs. 2006;24:403–412.
    1. Abiraj K, Mansi R, Tamma ML. et al. Bombesin antagonist-based radioligands for translational nuclear imaging of gastrin-releasing Peptide receptor-positive tumors. J Nucl Med. 2011;52:1970–1978.
    1. Mansi R, Wang X, Forrer F. et al. Evaluation of a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated bombesin-based radioantagonist for the labeling with single-photon emission computed tomography, positron emission tomography, and therapeutic radionuclides. Clin Cancer Res. 2009;15:5240–5249.
    1. Shokeen M, Anderson C. Molecular Imaging of Cancer with Copper-64 Radiopharmaceuticals and Positron Emission Tomography (PET) Accounts of Chemical Research. 2009;42:832–841.
    1. DeGrado TR, Reiman RE, Price DT, Wang S, Coleman RE. Pharmacokinetics and radiation dosimetry of 18F-fluorocholine. J Nucl Med. 2002;43:92–96.
    1. Jadvar H. Molecular Imaging of Prostate Cancer with PET. J Nucl Med. 2013;54:1685–1688.
    1. Schuster DM, Votaw JR, Nieh PT. et al. Initial experience with the radiotracer anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid with PET/CT in prostate carcinoma. J Nucl Med. 2007;48:56–63.
    1. Nanni C, Schiavina R, Boschi S. et al. Comparison of 18F-FACBC and 11C-choline PET/CT in patients with radically treated prostate cancer and biochemical relapse: preliminary results. Eur J Nucl Med Mol Imaging. 2013;40(Suppl 1):S11–17.
    1. Osborne JR, Green DA, Spratt DE. et al. A Prospective Pilot Study of 89Zr-J591/PSMA Positron Emission Tomography (PET) in Men with Localized Prostate Cancer Undergoing Radical Prostatectomy. J Urol. 2013 [epub ahead of print]
    1. Morris M, Pandit-Taskar N, Carrasquillo J, Phase I trial of zirconium 89 (Zr89) radiolabeled J591 in metastatic castration-resistant prostate cancer (mCRPC) J Clin Oncol. 2013. 31 (suppl 6)
    1. Afshar-Oromieh A, Malcher A, Eder M. et al. PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging. 2013;40:486–495.
    1. Cho SY, Gage KL, Mease RC. et al. Biodistribution, tumor detection, and radiation dosimetry of 18F-DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer. J Nucl Med. 2012;53:1883–1891.
    1. Afshar-Oromieh A, Zechmann CM, Malcher A, Comparison of PET imaging with a Ga-labelled PSMA ligand and F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2013.
    1. Larson SM, Morris M, Gunther I. et al. Tumor localization of 16beta-18F-fluoro-5alpha-dihydrotestosterone versus 18F-FDG in patients with progressive, metastatic prostate cancer. J Nucl Med. 2004;45:366–373.
    1. Schrecengost R, Knudsen KE. Molecular pathogenesis and progression of prostate cancer. Semin Oncol. 2013;40:244–258.
    1. Scher HI, Morris MJ, Larson S, Heller G. Validation and clinical utility of prostate cancer biomarkers. Nat Rev Clin Oncol. 2013;10:225–234.
    1. Craft JM, De Silva RA, Lears KA. et al. In vitro and in vivo evaluation of a 64Cu-labeled NOTA-Bn-SCN-Aoc-bombesin analogue in gastrin-releasing peptide receptor expressing prostate cancer. Nucl Med Biol. 2012;39:609–616.
    1. Chen X, Park R, Hou Y. et al. microPET and autoradiographic imaging of GRP receptor expression with 64Cu-DOTA-[Lys3]bombesin in human prostate adenocarcinoma xenografts. J Nucl Med. 2004;45:1390–1397.
    1. Prasanphanich AF, Nanda PK, Rold TL. et al. [64Cu-NOTA-8-Aoc-BBN(7-14)NH2] targeting vector for positron-emission tomography imaging of gastrin-releasing peptide receptor-expressing tissues. Proc Natl Acad Sci U S A. 2007;104:12462–12467.
    1. Van de Wiele C, Dumont F, Dierckx RA. et al. Biodistribution and dosimetry of (99m)Tc-RP527, a gastrin-releasing peptide (GRP) agonist for the visualization of GRP receptor-expressing malignancies. J Nucl Med. 2001;42:1722–1727.
    1. Ginj M, Zhang H, Waser B. et al. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proc Natl Acad Sci U S A. 2006;103:16436–16441.
    1. Schroeder RP, Muller C, Reneman S. et al. A standardised study to compare prostate cancer targeting efficacy of five radiolabelled bombesin analogues. Eur J Nucl Med Mol Imaging. 2010;37:1386–1396.
    1. Kahkonen E, Jambor I, Kemppainen J. et al. In Vivo Imaging of Prostate Cancer Using [68Ga]-Labeled Bombesin Analog BAY86-7548. Clin Cancer Res. 2013;19:5434–5443.
    1. Maddalena ME, Fox J, Chen J. et al. 177Lu-AMBA biodistribution, radiotherapeutic efficacy, imaging, and autoradiography in prostate cancer models with low GRP-R expression. J Nucl Med. 2009;50:2017–2024.
    1. Wild D, Frischknecht M, Zhang H. et al. Alpha- versus beta-particle radiopeptide therapy in a human prostate cancer model (213Bi-DOTA-PESIN and 213Bi-AMBA versus 177Lu-DOTA-PESIN) Cancer Res. 2011;71:1009–1018.
    1. Reubi JC, Wenger S, Schmuckli-Maurer J, Schaer JC, Gugger M. Bombesin receptor subtypes in human cancers: detection with the universal radioligand (125)I-[D-TYR(6), beta-ALA(11), PHE(13), NLE(14)] bombesin(6-14) Clin Cancer Res. 2002;8:1139–1146.
    1. Fleischmann A, Waser B, Reubi JC. Overexpression of gastrin-releasing peptide receptors in tumor-associated blood vessels of human ovarian neoplasms. Cell Oncol. 2007;29:421–433.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel