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Trial Lecture – time and place
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Adjudication committee
- First opponent: Group Leader Edward O'Neill, University of Oxford,
- Second opponent: Senior Principal Scientist Sofia Frost, Roche Innovation Center Welwyn,
- Third member and chair of the evaluation committee: Professor II Åslaug Helland, University of Oslo
Chair of the Defence
Professor II Jørgen Wesche, University of Oslo
Principal Supervisor
Associate professor Asta Juzeniene, OUS - Oslo University Hospital
Summary
Patients with metastatic prostate cancer experience reduced quality of life and poor prognosis. Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer, while remaining low in normal tissues, making it a suitable target for radioligand therapy. Radioligands have different biological and physical properties, but these differences are not always fully considered when selecting or optimizing treatment. Alpha particles are suitable for the treatment of micrometastatic disease because of their high energy over short distances compared to beta particles. Lead-212 (212Pb) is a promising candidate for radioligand therapy because its 10.6-hour half-life matches the pharmacokinetics of small-molecule ligands while its daughter products provide potent alpha-emitting cytotoxicity.
This doctoral work used in vitro, in vivo and ex vivo analyses to evaluate factors influencing the therapeutic efficacy of the PSMA-targeting [212Pb]Pb-AB001 in both localized and disseminated preclinical prostate cancer models.
Key determinants included PSMA expression, binding and internalization, administered activity and treatment regimen. Multicycle treatment responses were influenced by cycle number, treatment interval, per-cycle activity and cumulative activity, supporting schedule optimization in clinical protocols. The disseminated mouse model recapitulated clinically relevant metastases in bone, liver and lungs. [212Pb]Pb-AB001-targeted alpha-therapy showed significant advantages over the beta-emitting standard-of-care [177Lu]Lu-PSMA-617, supporting its potential for early metastatic disease and bone metastases.
Collectively, these data define key biological and treatment-related parameters governing response to PSMA-targeted alpha-therapy, and supports the clinical translation of [212Pb]Pb-AB001, which is now being evaluated in the clinical phase 1 ARTISAN trial.
Additional information
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