Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Richard P. Baum, Helios DKD Clinic Wiesbaden
- Second opponent: Senior Researcher Kinga Tkacz-Stachowska, IFE - Institute for Energy Technology
- Third member and chair of the evaluation committee: Professor II Jørgen Wesche, University of Oslo
Chair of the Defence
Associate Professor Viktor Berge, Faculty of Medicine, University of Oslo
Principal Supervisor
Scientist Asta Juzeniene, Department of Radiation Biology, Oslo University Hospital
Summary
Patients with metastatic castration-resistant prostate cancer (mCRPC) have bone and extraskeletal metastases, resulting in poor prognoses and reduced quality of life. The prostate-specific membrane antigen (PSMA) is overexpressed in mCRPC and can be targeted by radionuclide therapy. PSMA-targeted therapy with alpha emitters may deliver potent and local radiation more selectively to cancer cells than beta emitters and has recently gained remarkable interest for the treatment of mCRPC.
This thesis includes preclinical studies investigating the therapeutic potential and safety of the novel PSMA-targeting radioligand 212Pb-NG001 in various models of prostate cancer. The feasibility of a 224Ra/212Pb liquid generator for efficient 212Pb-labelling of the PSMA ligand was demonstrated. The generator allowed simple preparation of a radiopharmaceutical solution with dual alpha targeting properties: the natural bone-seeking 224Ra which targets bone metastases and the 212Pb-NG001 which targets PSMA-expressing circulating cancer cells and metastases. The accumulation of 224Ra in bones and 212Pb-NG001 in tumour sites was verified in tumour-bearing mice.
The 212Pb-NG001 accumulated rapidly in tumour and showed a high tumour retention over 24 hours, while it rapidly cleared from non-targeted tissues. The radioligand induced therapeutic effects both in a tumour model that resembles metastases with natural PSMA expression and blood-rich stroma, and in a tumour model with higher PSMA expression that mimics poorly vascularised metastases. The 212Pb-NG001 demonstrated high tolerability with no short- or long-term radiotoxicity observed at therapeutic relevant doses. In conclusion, 212Pb-NG001 is promising candidate for PSMA-TAT of mCRPC and warrant further exploration in early-phase clinical studies in patients.
Additional information
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