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，估计发病率为每10万人31例。VISION III期试验比较了针对PSMA的放射配体治疗（RLT）和标准治疗，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，放射性寡核苷酸[177Lu]Lu-PSMA-617有望很快获得欧洲上市许可。血液毒性是服用[177Lu]Lu-PSMA后已知的副作用之一。因此，表征β -发射器177Lu在患者外周血单个核细胞（PBMCs）中诱导的DNA损伤，并将这些结果与PET/CT成像、血液学参数和治疗反应相关联，是非常有意义的。使用生物标志物γ-H2AX+53BP1（也称为“DNA损伤焦点测定法”）进行DNA双链断裂（DSB）的可靠定量，特别是在低剂量照射后。因此，本研究一方面将在体外对血液进行辐照，以确定在规定的实验室条件下个体DNA损伤修复率；另一方面，在rlt期间进行血液采样，以确定体内DNA损伤诱导和修复的时间过程。前列腺癌患者采用[177Lu]Lu-PSMA治疗，按照标准临床惯例，4-6个周期，间隔6周。本项目旨在系统收集第一个和第三个治疗周期的功能影像学数据和临床、DNA损伤和修复数据，探讨重复治疗周期对患者pbmc中dsb诱导和修复的影响。此外，研究人员还将研究三个治疗周期后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表现（如肿瘤负荷、剂量学和治疗相关的血液学毒性）相关。因此，“DNA损伤焦点分析”的结果将与临床结果结合起来，以一种转化方法来评估这种新型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.