Forsøksdyr: Theranostic PSMA-based radiopharmaceuticals for metastatic prostate cancer

Godkjenningsdato 16.03.2020

Godkjenningsperiode 01.04.2020-31.03.2024

The prostate specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer (CRPC) with limited expression in healthy tissues. PSMA is a target for combined imaging diagnostics and targeted radioligand therapy (theranostics).

I. The purpose of the experiment/project:
This project focuses on preclinical studies of novel PSMA targeting ligands to deliver a positron emitter gallium-68 for imaging (patient selection) and a beta-particle emitter lead-212 as an in vivo generator of alpha-particles in comparisons radionuclides labelled to PSMA-617 ligand that have been used in preclinical and clinical studies. The project investigates the biodistribution, pharmacokinetics, dosimetry and therapeutic efficacy of the novel PSMA ligands labelled with radionuclides in immunodeficient mice bearing human CRPC (C4-2 cells) xenografts. Toxicity of the radiopharmaceuticals will be tested in immunocompetent mice (without xenografts).

II. The expected adverse effects on the animals:
The main adverse effects for the mice which may occur in these experiments are weight loss, a temporary reduction in platelets and white blood cell count and ulceration of the subcutaneous tumours. The chances of severe myelosuppression and nephrotoxicity, the major toxic effects of radionuclide treatment, are low. Radioactivities have been chosen based on earlier toxicological studies of the mentioned radionuclides alone in mice, as well as using novel PSMA ligands developed to reduce uptake in liver and bone marrow. In addition, pain arises as a result of cancer cell and radioligand injection, blood sampling, diagnostic or therapeutic procedures. The experiments may cause moderate pain and distress to the animals. Animal appearance, behaviour and clinical signs will be monitored daily. Mice will be euthanized immediately if they appear ill with any evidence of lethargy, “hunchback” appearance, weight loss exceeding 15% of their body weight, tumour diameter >1.2 cm, ulcer of tumour, or any noticeable abnormal appearance (ruffled fur in BALB/c mice).

III. The expected scientific benefits or benefits for society:
If the preclinical programs are successful, this could lead to clinical development of new and more effective radiopharmaceuticals for theranostic approach leading to personalization of the treatment by improving the selection of patients with PSMA positive metastatic CRPC (Gallium-68-PSMA-ligand) and their treatment outcomes (Lead-212-PSMA-ligand).

IV. The number of animals and species:
We are requesting 489 athymic mice, 200 NSG mice and 160 BALB/c mice to accomplish the proposed research objectives. The number of mice was determined based on earlier experiments and by statistical analysis.

V. How will the requirements for 3R be accomplished by the experiment/project:
The novel radioligands must be investigated in a suitable in vivo system to design and implement better theranostic strategies before clinical studies. No alternative biological systems can be found to obtain such information. Multiple in vitro studies have already been conducted by us to evaluate the PSMA-targeting properties, stability and therapeutic efficacy of the compounds before planning animal studies.The welfare of the mice will be checked daily and a score sheet will be used to monitor their health. We have good knowledge and experience with regards to tumour model, group size, timing of treatment etc.