The Gastrin-Releasing Peptide Receptor as Target for Molecular Imaging of Prostate Cancer: GRPR expression in prostate cancer and targeting with Bombesin-like radiopharmaceuticals

Hildo Ananias

The Gastrin-Releasing Peptide Receptor as Target for Molecular Imaging of Prostate Cancer: GRPR expression in prostate cancer and targeting with Bombesin-like radiopharmaceuticals

Vertaalde titel van de bijdrage: De Gastrin-Releasing Peptide Receptor as doel voor Moleculaire Beeldvorming van prostaatkanker: GRPR expressie in prostaatkanker en beeldvorming met bombesine-achtige radiofarmaca

Hildo Ananias

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Prostaatkanker is wereldwijd een veel voorkomende oorzaak van kanker, morbiditeit en sterfte. Nauwkeurige stagering is moeilijk en nog steeds suboptimaal. De Gastrin-Releasing Peptide Receptor (GRPR) is een tumor-geassocieerd antigeen dat tot overexpressie wordt gebracht in prostaatkanker. Gerichte beeldvorming van GRPR met nucleaire beeldvormende technieken kan worden bereikt door gebruik te maken van radioactief gelabelde bombesine analogen. In dit proefschrift wordt een overzicht gegeven van de klinische en preklinisch onderzoeken uitgevoerd met radioactief gelabelde bombesine analogen voor de beeldvorming van prostaatkanker. Verder is de expressie van GRPR en diverse andere antigenen in prostaatkanker metastasen en post-radiotherapie lokaal recidief prostaatkanker bepaald door immunohistochemische kleuring van humane weefselmonsters. GRPR bleek bij 85,7% van de lymfkliermetastasen en bij 52,9% van de botmetastasen van prostaatkanker voor te komen. Hoewel expressie van GRPR werd waargenomen al het prostaatkankerweefsel met lokaal recidief, was het tumor onderscheidend vermogen van GRPR nihil door gelijke GRPR kleuring van goedaardig prostaatstroma.
Ook twee nieuwe bombesine-achtige radiofarmaca, 99mTc-HYNIC(tricine/TPPTS)-Aca-Bombesin(7-14) en de homodimeer 111In-DOTA-[Aca-Bombesin(7-14)]2, werden onderzocht op geschiktheid voor beeldvorming in prostaatkanker xenograft muismodellen. Beide radiofarmaca toonden goede en specifieke tumoropname, hoge stabiliteit in menselijk serum en hoog tumor-achtergrond contrast. Gebaseerd op deze resultaten werd 99mTc-HYNIC(tricine/TPPTS)-Aca-Bombesin(7-14) ook geëvalueerd met SPECT/CT bij acht prostaatkankerpatiënten met bewezen ziekte. Er werd geen opname in de prostaat waargenomen als gevolg van slechte in vivo stabiliteit van het radiofarmacon. Deze bevinding is in strijd met de uitstekende resultaten van de preklinische in vitro stabiliteit tests in humaan serum in eerder uitgevoerd en vereist verder onderzoek.

Vertaalde titel van de bijdrage	De Gastrin-Releasing Peptide Receptor as doel voor Moleculaire Beeldvorming van prostaatkanker: GRPR expressie in prostaatkanker en beeldvorming met bombesine-achtige radiofarmaca
Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	de Jong, Igle Jan, Supervisor Elsinga, Philip, Supervisor Dierckx, Rudi, Supervisor
Datum van toekenning	15-okt.-2014
Plaats van publicatie	[S.l.]
Uitgever	[S.n.]
Gedrukte ISBN's	978-90-367-7103-0
Elektronische ISBN's	978-90-367-7102-3
Status	Published - 2014

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title = "The Gastrin-Releasing Peptide Receptor as Target for Molecular Imaging of Prostate Cancer: GRPR expression in prostate cancer and targeting with Bombesin-like radiopharmaceuticals",

abstract = "Worldwide, prostate cancer (PCa) is a frequent cause of cancer, morbidity and death. Accurate staging poses several dilemmas and is still suboptimal. The Gastrin-Releasing Peptide Receptor (GRPR) is a tumor-associated antigen overexpressed in PCa. Targeted imaging of GRPR with nuclear imaging techniques can be achieved by using radiolabeled bombesin analogues. In this dissertation an overview is provided of the clinical and preclinical research performed on PCa imaging with radiolabeled bombesin analogues. Furthermore the expression of GRPR and several other target antigens in PCa metastases and post-radiotherapy locally recurrent PCa was determined by immunohistochemical staining of human tissue specimens. GRPR appeared to be expressed in 85.7% of lymph node metastases and in 52.9% of bone metastases of PCa. Although expression of GRPR was observed in 100% of locally recurrent PCa tissue samples, the tumor distinctiveness of GRPR in irradiated recurrent PCa was nil due to equal GRPR staining of benign stroma.Also two new bombesin-based radiopharmaceuticals, 99mTc-HYNIC(tricine/TPPTS)-Aca-Bombesin(7-14) and the homodimer 111In-DOTA-[Aca-Bombesin (7-14)]2, were investigated for their tumor targeting properties in PCa xenograft mouse models. Both compounds demonstrated good and specific tumor uptake, combined with high stability in human serum and high tumor-to-background contrast. Based on these results 99mTc-HYNIC(tricine/TPPTS)-Aca-Bombesin(7-14) was also evaluated with SPECT/CT in eight patients with proven disease. No uptake in the prostate was observed due to poor in vivo stability of the radiopharmaceutical. This finding is conflicting with the excellent results of the preclinical in vitro stability test in human serum performed previously and warrants further research.",

author = "Hildo Ananias",

year = "2014",

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school = "University of Groningen",

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T1 - The Gastrin-Releasing Peptide Receptor as Target for Molecular Imaging of Prostate Cancer

T2 - GRPR expression in prostate cancer and targeting with Bombesin-like radiopharmaceuticals

AU - Ananias, Hildo

PY - 2014

Y1 - 2014

N2 - Worldwide, prostate cancer (PCa) is a frequent cause of cancer, morbidity and death. Accurate staging poses several dilemmas and is still suboptimal. The Gastrin-Releasing Peptide Receptor (GRPR) is a tumor-associated antigen overexpressed in PCa. Targeted imaging of GRPR with nuclear imaging techniques can be achieved by using radiolabeled bombesin analogues. In this dissertation an overview is provided of the clinical and preclinical research performed on PCa imaging with radiolabeled bombesin analogues. Furthermore the expression of GRPR and several other target antigens in PCa metastases and post-radiotherapy locally recurrent PCa was determined by immunohistochemical staining of human tissue specimens. GRPR appeared to be expressed in 85.7% of lymph node metastases and in 52.9% of bone metastases of PCa. Although expression of GRPR was observed in 100% of locally recurrent PCa tissue samples, the tumor distinctiveness of GRPR in irradiated recurrent PCa was nil due to equal GRPR staining of benign stroma.Also two new bombesin-based radiopharmaceuticals, 99mTc-HYNIC(tricine/TPPTS)-Aca-Bombesin(7-14) and the homodimer 111In-DOTA-[Aca-Bombesin (7-14)]2, were investigated for their tumor targeting properties in PCa xenograft mouse models. Both compounds demonstrated good and specific tumor uptake, combined with high stability in human serum and high tumor-to-background contrast. Based on these results 99mTc-HYNIC(tricine/TPPTS)-Aca-Bombesin(7-14) was also evaluated with SPECT/CT in eight patients with proven disease. No uptake in the prostate was observed due to poor in vivo stability of the radiopharmaceutical. This finding is conflicting with the excellent results of the preclinical in vitro stability test in human serum performed previously and warrants further research.

AB - Worldwide, prostate cancer (PCa) is a frequent cause of cancer, morbidity and death. Accurate staging poses several dilemmas and is still suboptimal. The Gastrin-Releasing Peptide Receptor (GRPR) is a tumor-associated antigen overexpressed in PCa. Targeted imaging of GRPR with nuclear imaging techniques can be achieved by using radiolabeled bombesin analogues. In this dissertation an overview is provided of the clinical and preclinical research performed on PCa imaging with radiolabeled bombesin analogues. Furthermore the expression of GRPR and several other target antigens in PCa metastases and post-radiotherapy locally recurrent PCa was determined by immunohistochemical staining of human tissue specimens. GRPR appeared to be expressed in 85.7% of lymph node metastases and in 52.9% of bone metastases of PCa. Although expression of GRPR was observed in 100% of locally recurrent PCa tissue samples, the tumor distinctiveness of GRPR in irradiated recurrent PCa was nil due to equal GRPR staining of benign stroma.Also two new bombesin-based radiopharmaceuticals, 99mTc-HYNIC(tricine/TPPTS)-Aca-Bombesin(7-14) and the homodimer 111In-DOTA-[Aca-Bombesin (7-14)]2, were investigated for their tumor targeting properties in PCa xenograft mouse models. Both compounds demonstrated good and specific tumor uptake, combined with high stability in human serum and high tumor-to-background contrast. Based on these results 99mTc-HYNIC(tricine/TPPTS)-Aca-Bombesin(7-14) was also evaluated with SPECT/CT in eight patients with proven disease. No uptake in the prostate was observed due to poor in vivo stability of the radiopharmaceutical. This finding is conflicting with the excellent results of the preclinical in vitro stability test in human serum performed previously and warrants further research.

M3 - Thesis fully internal (DIV)

SN - 978-90-367-7103-0

PB - [S.n.]

CY - [S.l.]

ER -