The Cancer Research Foundation Czech Republic has long been dedicated to supporting scientists and their research projects. In November 2024, the three-day Czech Annual Cancer Research Meeting took place in Olomouc, attracting more than 300 participants.
As one of the event's key partners, the foundation awarded financial prizes for the best oral presentation and poster presentation. Zbyněk Nový was awarded for the best oral presentation on his work on "Preclinical assessment of enhanced blood retention and tumor uptake PSMAtargeting 225Ac-labeled". Congratulations!
Abstract
Introduction: The prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer at significantly higher levels compared to healthy tissue. Therefore, PSMA has emerged as very suitable target for molecular imaging as well as targeted radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC). In this study, we have investigated the in vivo behavior of two novel macropa-based PSMA inhibitors, namely [225Ac]Ac-mcp-D-PSMA and [225Ac]Ac-mcp-M-alb-PSMA modified with albumin binding moiety. The main motivation behind this project was to improve tumor uptake and thus therapeutic efficacy of those novel 225Ac-PSMA inhibitors.
Methods: We have performed in vivo studies involving long-term toxicity study in healthy mice with subsequent immunohistochemical examinations of kidneys and salivary glands. We have also done therapeutic efficacy study in LNCaP-tumor bearing animals employing three different doses (5/15/45 kBq/mouse). Kidneys, livers and tumors were examined using immunohistochemical staining methods to detect PSMA expression, DNA damage (γH2AX), proliferation status (Ki67) and necrosis (H&E).
Results: The toxicity study have not revealed any significant toxic effect in studied parameters. Insignificant DNA damage was observed in the kidney tissue compared to the untreated controls. The therapy study showed no significant effect of two lower doses (5 and 15 kBq/animal) onto tumor volume or survival. The dose of 45 kBq/mouse had significant impact to both mentioned parameters, whereas [225Ac]Ac-mcp-M-alb-PSMA performed better than other two 225Ac-PSMA inhibitors.
Conclusion: In vivo experiments in healthy mice showed very low toxicity of tested PSMA inhibitors. Histological examination of the organs in therapy study confirmed substantial DNA damage in the tumor tissue of mice injected with both studied novel 225Ac-compounds, on the other hand the same parameter revealed only low DNA harm in the kidneys. The therapeutic efficacy of novel compounds was comparable to gold standard 225Ac-PSMA-617, in case of [225Ac]Ac-mcp-M-alb-PSMA seemed to be even higher.
Acknowledgement: This work was funded by The project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) - Funded by European Union - Next Generation EU.
The Czech Annual Cancer Research Meeting focused on the latest advances in cancer research, molecular pathology and predictive oncology. ➡ More info www.cancermeeting.cz
