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

前列腺癌是世界上最常见的肿瘤疾病之一，估计每10万人中有31例发病率。VISION III期试验将针对PSMA的放射配基治疗(RLT)与治疗标准进行了比较，在前列腺癌患者中显示出非常有希望的临床治疗反应。因此，放射性配体[177Lu]Lu-PSMA-617有望很快在欧洲上市。血液毒性是使用[177 Lu]Lu-PSMA后已知的副作用之一。因此，研究贝塔辐射体177Lu对患者外周血单个核细胞(PBMCs)的DNA损伤，将其与PET/CT成像、血液学参数和治疗反应相关联，是非常有意义的。DNA双链断裂的可靠定量，特别是在低剂量照射后，使用生物标记物γ-H2AX+53BP1(也称为DNA损伤焦点分析)进行。因此，本研究一方面通过体外照射血液来确定特定实验室条件下个体的DNA损伤修复率，另一方面在RLTS过程中采集血液以确定体内DNA损伤诱导和修复的时间进程。前列腺癌患者的[177Lu]Lu-PSMA将按照标准的临床实践进行治疗，每4-6个周期，间隔6周。该项目的目的是系统地收集第一个和第三个治疗周期的功能成像数据和临床以及DNA损伤和修复数据，以调查重复治疗周期对患者PBMCs中DSB诱导和修复的影响。此外，还将调查三个周期后DSB的诱导和修复是否可以预测治疗结果和副作用，以及患者的DNA损伤是否与其他临床结果相关，如肿瘤负担、剂量学和与治疗相关的血液毒性。因此，DNA损伤焦点分析的结果将与临床结果结合在一起，以翻译的方法评估这种新的治疗方式的治疗结果和副作用。

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.