Can radioligand therapy-induced DNA damage in prostate cancer patients predict treatment outcome and side effects?

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Prostate cancer is one of the most common tumor diseases worldwide, with an estimated incidence rate of 31 cases per 100,000 individuals. The VISION phase III trial, which compares radioligand therapy (RLT) targeting PSMA against the standard of care, showed very promising clinical treatment response in prostate cancer patients. Therefore, a European marketing authorization for the radioligand [177Lu]Lu-PSMA-617 is expected soon.Hematotoxicity is one of the known side effects after administration of [177Lu]Lu-PSMA. Therefore, it is of great interest to characterize the DNA damage, induced by the beta emitter 177Lu in patients’ peripheral blood mononuclear cells (PBMCs) to correlate these results with PET/CT imaging, hematologic parameters, and treatment response. Reliable quantification of DNA double-strand breaks (DSB), especially after low-dose irradiation, is performed using the biomarkers γ-H2AX+53BP1 (also called "DNA damage focus assay"). Therefore, the study will involve, on the one hand, irradiation of blood ex vivo to determine the individual DNA damage repair rates under defined laboratory conditions and, on the other hand, blood sampling during RLTs to determine in vivo the time course of damage induction and repair of DNA damage.Treatment of prostate cancer patients with [177Lu]Lu-PSMA will be performed according to standard clinical practice in 4-6 cycles, 6 weeks apart. The aim of the project is to systematically collect functional imaging data and clinical, and DNA damage and repair data for the first and third therapy cycle to investigate the impact of repeated therapy cycles on the induction and repair of DSBs in patients' PBMCs. Furthermore, it will be investigated whether the induction and repair of DSBs after three cycles of treatment can predict treatment outcome and side effects, and whether DNA damage in patients correlates with other clinical findings such as tumor burden, dosimetry, and treatment-related hematologic toxicity.The results of the "DNA damage focus assay" will thus be combined with clinical findings in a translational approach to o assess treatment outcome and side effects of this novel treatment modality.