uu.seUppsala universitets publikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Trastuzumab cotreatment improves survival of mice with PC-3 prostate cancer xenografts treated with the GRPR antagonist 177Lu-DOTAGA-PEG2-RM26
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.ORCID-id: 0000-0001-7921-3268
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands.
NCSR Demokritos, INRASTES, Mol Radiopharm, Athens, Greece.
Visa övriga samt affilieringar
2019 (Engelska)Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, nr 12, s. 3347-3358Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Gastrin-releasing peptide receptors (GRPRs) are overexpressed in prostate cancer and are suitable for targeted radionuclidetherapy (TRT). We optimized the bombesin-derived GRPR-antagonist PEG2-RM26 for labeling with 177Lu and further determinedthe effect of treatment with 177Lu-labeled peptide alone or in combination with the anti-HER2 antibody trastuzumab in amurine model. The PEG2-RM26 analog was coupled to NOTA, NODAGA, DOTA and DOTAGA chelators. The peptide-chelatorconjugates were labeled with 177Lu and characterized in vitro and in vivo. A preclinical therapeutic study was performed in PC-3xenografted mice. Mice were treated with intravenous injections (6 cycles) of (A) PBS, (B) DOTAGA-PEG2-RM26, (C) 177LuDOTAGA-PEG2-RM26, (D) trastuzumab or (E) 177Lu-DOTAGA-PEG2-RM26 in combination with trastuzumab. 177Lu-DOTAGA-PEG2-RM26 demonstrated quantitative labeling yield at high molar activity (450 GBq/μmol), high in vivo stability (5 min pi >98% ofradioligand remained when coinjected with phosphoramidon), high affinity to GRPR (KD = 0.4 0.2 nM), and favorablebiodistribution (1 hr pi tumor uptake was higher than in healthy tissues, including the kidneys). Therapy with 177Lu-DOTAGAPEG2-RM26 induced a significant inhibition of tumor growth. The median survival for control groups was significantly shorterthan for treated groups (Group C 66 days, Group E 74 days). Trastuzumab together with radionuclide therapy significantlyimproved survival. No treatment-related toxicity was observed. In conclusion, based on in vitro and in vivo characterization ofthe four 177Lu-labeled PEG2-RM26 analogs, we concluded that 177Lu-DOTAGA-PEG2-RM26 was the most promising analog forTRT. Radiotherapy using 177Lu-DOTAGA-PEG2-RM26 effectively inhibited tumor growth in vivo in a murine prostate cancermodel. Anti-HER2 therapy additionally improved survival.

Ort, förlag, år, upplaga, sidor
2019. Vol. 145, nr 12, s. 3347-3358
Nyckelord [en]
radionuclide therapy, GRPR, HER2, prostate cancer, lutetium-177
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
URN: urn:nbn:se:uu:diva-389561DOI: 10.1002/ijc.32401ISI: 000491231500016PubMedID: 31077356OAI: oai:DiVA.org:uu-389561DiVA, id: diva2:1337863
Forskningsfinansiär
Cancerfonden, CAN2014-474Cancerfonden, CAN 2018/436Cancerfonden, CAN2015/350Cancerfonden, CAN 2017/425Vetenskapsrådet, 2015-02509Vetenskapsrådet, 2015-02353Tillgänglig från: 2019-07-17 Skapad: 2019-07-17 Senast uppdaterad: 2019-11-08Bibliografiskt granskad
Ingår i avhandling
1. Prostate cancer theranostics using GRPR antagonist RM26
Öppna denna publikation i ny flik eller fönster >>Prostate cancer theranostics using GRPR antagonist RM26
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The malignant transformation of cells is often associated with an alteration of their molecular phenotype, resulting in overexpression of several cell surface proteins. Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are examples of such pro-teins that are expressed at a high density in prostate cancer. GRPR is primarily expressed in earlier stages of prostate cancer and tends to decrease with disease progression. This expression pattern indicates that GRPR could be a promising target for imaging and treatment of oligometa-static prostate cancer, an early step in prostate cancer progression characterized by limited meta-static spread. In contrast, the expression of PSMA increases with cancer progression and is significantly upregulated as tumors dedifferentiate into higher grade, in androgen-insensitive and metastatic lesions.

This thesis is based on five original articles (papers I-V) and focuses on the preclinical de-velopment of radiotracers for imaging and treatment of prostate cancer. The work can be divided into three distinct parts: (1) the development and optimization of GRPR-antagonist RM26 for high contrast PET and SPECT imaging of oligometastatic prostate cancer (papers I-III), (2) the preclinical evaluation of 177Lu-labeled RM26 as a potential candidate for peptide receptor radionuclide therapy (PRRT) in GRPR-expressing tumors, alone or in combination with anti-HER2 antibody trastuzumab (paper IV), and (3) the development of a bispecific heterodimer targeting both PSMA and GRPR in prostate cancer (paper V).

We have demonstrated that the in vitro and in vivo properties of GRPR antagonist RM26 are strongly influenced by the choice of chelator-radionuclide complex and that long-lived radionuclides are desirable for high-contrast imaging. Furthermore, our data indicate that 55Co-NOTA-PEG2-RM26 has remarkable potential for next-day high-contrast PET imaging of GRPR-expressing tumors. Experimental PRRT using 177Lu-DOTAGA-PEG2-RM26 resulted in a pronounced inhibition of tumor growth and a significantly longer median survival. Interestingly, survival was further improved when trastuzumab was co-injected with 177Lu-DOTAGA-PEG2-RM26. These data indicate that blocking HER2 with trastuzumab decreased the repairing ability of irradiated cells. Finally, we developed a heterodimer (NOTA-DUPA-RM26) for imaging GRPR and PSMA expression in prostate cancer shortly after administration.

In conclusion, we have successfully developed and preclinically evaluated radioconjugates for GRPR-directed theranostics in oligometastatic prostate cancer using the bombesin antagonistic analog RM26.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 80
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 274
Nyckelord
Gastrin-releasing peptide receptor (GRPR), Bombesin, Prostate-specific membrane antigen (PSMA), Antagonist, Radionuclide molecular imaging, Theranostics, Peptide receptor radionuclide therapy (PRRT).
Nationell ämneskategori
Läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-389563 (URN)978-91-513-0695-7 (ISBN)
Disputation
2019-09-14, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-08-23 Skapad: 2019-07-17 Senast uppdaterad: 2019-09-17

Open Access i DiVA

fulltext(2153 kB)110 nedladdningar
Filinformation
Filnamn FULLTEXT01.pdfFilstorlek 2153 kBChecksumma SHA-512
3b843a6289e69b4ac3f0b8fbafdc6939d6771080ec0a56f35dcf0b931abf0972b23c73eeda55b630c2f4224624d93ad5624de018d97cc5457e74044f303289a5
Typ fulltextMimetyp application/pdf

Övriga länkar

Förlagets fulltextPubMed

Personposter BETA

Mitran, BogdanRinne, Sara S.Altai, MohamedVorobyeva, AnzhelikaLarhed, MatsTolmachev, VladimirRosenström, UlrikaOrlova, Anna

Sök vidare i DiVA

Av författaren/redaktören
Mitran, BogdanRinne, Sara S.Altai, MohamedVorobyeva, AnzhelikaLarhed, MatsTolmachev, VladimirRosenström, UlrikaOrlova, Anna
Av organisationen
TheranosticsMedicinsk strålningsvetenskapPreparativ läkemedelskemiScience for Life Laboratory, SciLifeLab
I samma tidskrift
International Journal of Cancer
Cancer och onkologi

Sök vidare utanför DiVA

GoogleGoogle Scholar
Totalt: 110 nedladdningar
Antalet nedladdningar är summan av nedladdningar för alla fulltexter. Det kan inkludera t.ex tidigare versioner som nu inte längre är tillgängliga.

doi
pubmed
urn-nbn

Altmetricpoäng

doi
pubmed
urn-nbn
Totalt: 172 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf