Positron Emission Tomography (PET) Imaging of Prostate Cancer with a Gastrin Releasing Peptide Receptor Antagonist - from Mice to Men

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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)-PEG ₄-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-LeuNH ₂] 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.

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Most cited references 29

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International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states.

Richard V. Benya, Miranda Spindel, Anja T R Jensen … (2008)

The mammalian bombesin receptor family comprises three G protein-coupled heptahelical receptors: the neuromedin B (NMB) receptor (BB(1)), the gastrin-releasing peptide (GRP) receptor (BB(2)), and the orphan receptor bombesin receptor subtype 3 (BRS-3) (BB(3)). Each receptor is widely distributed, especially in the gastrointestinal (GI) tract and central nervous system (CNS), and the receptors have a large range of effects in both normal physiology and pathophysiological conditions. The mammalian bombesin peptides, GRP and NMB, demonstrate a broad spectrum of pharmacological/biological responses. GRP stimulates smooth muscle contraction and GI motility, release of numerous GI hormones/neurotransmitters, and secretion and/or hormone release from the pancreas, stomach, colon, and numerous endocrine organs and has potent effects on immune cells, potent growth effects on both normal tissues and tumors, potent CNS effects, including regulation of circadian rhythm, thermoregulation; anxiety/fear responses, food intake, and numerous CNS effects on the GI tract as well as the spinal transmission of chronic pruritus. NMB causes contraction of smooth muscle, has growth effects in various tissues, has CNS effects, including effects on feeding and thermoregulation, regulates thyroid-stimulating hormone release, stimulates various CNS neurons, has behavioral effects, and has effects on spinal sensory transmission. GRP, and to a lesser extent NMB, affects growth and/or differentiation of various human tumors, including colon, prostate, lung, and some gynecologic cancers. Knockout studies show that BB(3) has important effects in energy balance, glucose homeostasis, control of body weight, lung development and response to injury, tumor growth, and perhaps GI motility. This review summarizes advances in our understanding of the biology/pharmacology of these receptors, including their classification, structure, pharmacology, physiology, and role in pathophysiological conditions.

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Imaging prostate cancer: a multidisciplinary perspective.

S A Leibel, Peter T. Scardino, Hedvig Hricak … (2007)

The major goal for prostate cancer imaging in the next decade is more accurate disease characterization through the synthesis of anatomic, functional, and molecular imaging information. No consensus exists regarding the use of imaging for evaluating primary prostate cancers. Ultrasonography is mainly used for biopsy guidance and brachytherapy seed placement. Endorectal magnetic resonance (MR) imaging is helpful for evaluating local tumor extent, and MR spectroscopic imaging can improve this evaluation while providing information about tumor aggressiveness. MR imaging with superparamagnetic nanoparticles has high sensitivity and specificity in depicting lymph node metastases, but guidelines have not yet been developed for its use, which remains restricted to the research setting. Computed tomography (CT) is reserved for the evaluation of advanced disease. The use of combined positron emission tomography/CT is limited in the assessment of primary disease but is gaining acceptance in prostate cancer treatment follow-up. Evidence-based guidelines for the use of imaging in assessing the risk of distant spread of prostate cancer are available. Radionuclide bone scanning and CT supplement clinical and biochemical evaluation (prostate-specific antigen [PSA], prostatic acid phosphate) for suspected metastasis to bones and lymph nodes. Guidelines for the use of bone scanning (in patients with PSA level > 10 ng/mL) and CT (in patients with PSA level > 20 ng/mL) have been published and are in clinical use. Nevertheless, changes in practice patterns have been slow. This review presents a multidisciplinary perspective on the optimal role of modern imaging in prostate cancer detection, staging, treatment planning, and follow-up.

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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.

Michael P. Holt, Mario Eisenberger, Robert F. Dannals … (2012)

Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-(18)F-fluorobenzyl-L-cysteine ((18)F-DCFBC) could image an experimental model of PSMA-positive PCa using PET. Here, we describe the initial clinical experience and radiation dosimetry of (18)F-DCFBC in men with metastatic PCa. Five patients with radiologic evidence of metastatic PCa were studied after the intravenous administration of 370 MBq (10 mCi) of (18)F-DCFBC. Serial PET was performed until 2 h after administration. Time-activity curves were generated for selected normal tissues and metastatic foci. Radiation dose estimates were calculated using OLINDA/EXM 1.1. Most vascular organs demonstrated a slow decrease in radioactivity concentration over time consistent with clearance from the blood pool, with primarily urinary radiotracer excretion. Thirty-two PET-positive suspected metastatic sites were identified, with 21 concordant on both PET and conventional imaging for abnormal findings compatible with metastatic disease. Of the 11 PET-positive sites not identified on conventional imaging, most were within the bone and could be considered suggestive for the detection of early bone metastases, although further validation is needed. The highest mean absorbed dose per unit administered radioactivity (μGy/MBq) was in the bladder wall (32.4), and the resultant effective dose was 19.9 ± 1.34 μSv/MBq (mean ± SD). Although further studies are needed for validation, our findings demonstrate the potential of (18)F-DCFBC as a new positron-emitting imaging agent for the detection of metastatic PCa. This study also provides dose estimates for (18)F-DCFBC that are comparable to those of other PET radiopharmaceuticals such as (18)F-FDG.

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Author and article information

Journal

Journal ID (nlm-ta): Theranostics

Journal ID (iso-abbrev): Theranostics

Journal ID (publisher-id): thno

Title: Theranostics

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1838-7640

Publication date Collection: 2014

Publication date (Electronic): 1 February 2014

Volume: 4

Issue: 4

Pages: 412-419

Affiliations

1. Department of Nuclear Medicine, University Hospital Freiburg, Germany.

2. Department of Radiation Oncology, University Hospital Freiburg, Germany.

3. Department of Urology, University Hospital Freiburg, Germany.

4. Department of Radiology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.

5. German Cancer Consortium (DKTK).

6. Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Switzerland.

7. Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Author notes

✉ Corresponding author: Gesche Wieser, Hugstetter Straße 55, 79102 Freiburg i. Br., Germany, Phone: +49-761-27039160, Fax: +49-761-27039300, gesche.wieser@ 123456uniklinik-freiburg.de .

* First authors (both authors contributed equally to this work): Gesche Wieser (resident, MD) and Rosalba Mansi (PhD), Hugstetter Straße 55, 79102 Freiburg i. Br., Germany, Phone: +49-761-27039160, Fax: +49-761-27039300, gesche.wieser@uniklinik-freiburg.de or rosalba.mansi@uniklinik-freiburg.de

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

Article

Publisher ID: thnov04p0412

DOI: 10.7150/thno.7324

PMC ID: 3936293

PubMed ID: 24578724

SO-VID: bf02377c-29d0-40e1-ba5d-0e757260d3bd

Copyright © © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.

Positron Emission Tomography (PET) Imaging of Prostate Cancer with a Gastrin Releasing Peptide Receptor Antagonist - from Mice to Men

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Electron Channelling Contrast Imaging (ECCI)

Most cited references 29

International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states.

Imaging prostate cancer: a multidisciplinary perspective.

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.

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