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

放射配体治疗引起的前列腺癌患者 DNA 损伤能否预测治疗结果和副作用？

• 批准号: 509851852
• 负责人: Dr. Uta Eberlein
• 金额: --
• 依托单位: Klinik und Poliklinik für Nuklearmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/509851852?language=en
• 关键词: radioligand; therapy; induced; DNA; damage

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.

前列腺癌是全球最常见的肿瘤疾病之一，估计发病率为每10万人31例。VISION III期试验比较了靶向PSMA的放射性配体治疗（RLT）与标准治疗，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，放射性配体[177 Lu]Lu-PSMA-617有望很快获得欧洲上市许可。血液毒性是[177 Lu]Lu-PSMA给药后的已知副作用之一。因此，表征由β发射体177 Lu在患者的外周血单核细胞（PBMC）中诱导的DNA损伤以将这些结果与PET/CT成像、血液学参数和治疗反应相关联是非常有意义的。DNA双链断裂（DSB）的可靠定量，特别是在低剂量照射后，使用生物标志物γ-H2 AX +53 BP 1（也称为“DNA损伤灶测定”）进行。因此，该研究将涉及，一方面，离体照射血液以确定在定义的实验室条件下的个体DNA损伤修复率，另一方面，用[177 Lu]Lu-PSMA治疗前列腺癌患者将根据标准临床实践在4- 10年中进行，6个周期，间隔6周。该项目的目的是系统地收集第一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，以研究重复治疗周期对患者PBMC中DSB诱导和修复的影响。此外，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发现相关，如肿瘤负荷、剂量测定、和治疗相关的血液学毒性。“DNA损伤病灶测定”的结果因此，将与转化方法中的临床发现相结合，以评估这种新型治疗方式的治疗结果和副作用。