DNA依赖性蛋白激酶抑制剂培铂西替尼增强镥基放射免疫疗法在前列腺癌和肾细胞癌临床前模型中的疗效。
DNA-Dependent Protein Kinase Inhibitor Peposertib Enhances Efficacy of Lu-Based Radioimmunotherapy in Preclinical Models of Prostate and Renal Cell Carcinoma.
作者信息
Johnstone Cameron N, Osellame Laura D, Cao Zhipeng, McDonald Alexander F, Rigopoulos Angela, Burvenich Ingrid J G, Wichmann Christian W, Guo Nancy, Ivashkevich Alesia N, Wheatcroft Michael P, Yan Edwin B, Zimmermann Astrid, Zenke Frank T, Sirrenberg Christian, Scott Fiona E, Scott Andrew M
机构信息
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.
School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia.
出版信息
J Nucl Med. 2025 Mar 3;66(3):385-390. doi: 10.2967/jnumed.124.268695.
Novel radiation sensitizers, including inhibitors targeting DNA damage response, have been developed to enhance the efficacy of anticancer treatments that induce DNA damage in cancer cells. Peposertib, a potent, selective, and orally administered inhibitor of DNA-dependent protein kinase, impedes the nonhomologous end-joining mechanism for DNA double-strand break (DSB) repair. We investigated radioimmunotherapy alone or with peposertib in preclinical models of renal cell carcinoma (RCC) or prostate cancer. Lu-DOTA-girentuximab (targeting carbonic anhydrase IX) or Lu-DOTA-rosopatamab (targeting prostate-specific membrane antigen) was used to deliver β-radiation to tumors via a single intravenous dose (3 or 6 MBq) in mice bearing SK-RC-52 RCC or LNCaP prostate cancer xenografts, respectively. Peposertib (50 mg/kg daily for 14 d) was administered via oral gavage. Biodistribution and in vivo imaging of Lu-based radioimmunotherapy were performed for both preclinical models. Tumor growth and body weight were monitored until the endpoint. Assessment of DNA damage was performed by measuring DSBs through analysis of γH2AX foci formation in tumor sections. Ex vivo biodistribution and in vivo SPECT/MRI revealed excellent tumor uptake of each radiopharmaceutical. Mouse body weight was stable in all treatment arms. Peposertib alone did not show a significant antitumor effect. The addition of peposertib to Lu-DOTA-girentuximab showed enhanced antitumor efficacy compared with Lu-DOTA-girentuximab alone in the SK-RC-52 animal model, with a 4 of 4 complete response rate in the Lu-DOTA-girentuximab (6 MBq) plus peposertib arm. Peposertib combined with low-dose Lu-DOTA-girentuximab (3 MBq) demonstrated antitumor activity comparable to Lu-DOTA-girentuximab (6 MBq) monotherapy. In the LNCaP prostate cancer model, the combination of Lu-DOTA-rosopatamab (6 MBq) and peposertib achieved a 3 of 4 complete response rate. Increased DSBs were observed with the addition of peposertib to Lu-based radioimmunotherapy. The combination of peposertib with Lu-based radioimmunotherapy was well tolerated in preclinical models of RCC and prostate cancer. Our findings suggest a synergistic effect between peposertib and Lu-based radioimmunotherapy, wherein peposertib enhanced the efficacy of radioimmunotherapy. This synergy indicates the potential to reduce the necessary dose of radioimmunotherapy for effective cancer treatment.
包括靶向DNA损伤反应抑制剂在内的新型放射增敏剂已被开发出来，以提高在癌细胞中诱导DNA损伤的抗癌治疗的疗效。培泊替尼是一种强效、选择性且口服的DNA依赖性蛋白激酶抑制剂，它会阻碍DNA双链断裂（DSB）修复的非同源末端连接机制。我们在肾细胞癌（RCC）或前列腺癌的临床前模型中研究了单独使用放射免疫疗法或联合培泊替尼的情况。分别使用1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）-吉妥昔单抗（靶向碳酸酐酶IX）或1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）-罗索帕他单抗（靶向前列腺特异性膜抗原），通过单次静脉注射剂量（3或6兆贝可）分别将β射线递送至携带SK-RC-52肾细胞癌或LNCaP前列腺癌异种移植瘤的小鼠的肿瘤中。通过口服灌胃给予培泊替尼（每日50毫克/千克，共14天）。对两种临床前模型进行了基于镥的放射免疫疗法的生物分布和体内成像。监测肿瘤生长和体重直至实验终点。通过分析肿瘤切片中γH2AX焦点形成来测量DSB，从而进行DNA损伤评估。体外生物分布和体内单光子发射计算机断层扫描/磁共振成像（SPECT/MRI）显示每种放射性药物在肿瘤中的摄取良好。所有治疗组的小鼠体重均稳定。单独使用培泊替尼未显示出显著的抗肿瘤作用。在SK-RC-52动物模型中，与单独使用1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）-吉妥昔单抗相比，培泊替尼与1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）-吉妥昔单抗联合使用显示出增强的抗肿瘤疗效，在1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）-吉妥昔单抗（6兆贝可）加培泊替尼组中完全缓解率为4/4。培泊替尼与低剂量1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）-吉妥昔单抗（3兆贝可）联合使用显示出与1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）-吉妥昔单抗（6兆贝可）单药治疗相当的抗肿瘤活性。在LNCaP前列腺癌模型中，1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）-罗索帕他单抗（6兆贝可）与培泊替尼联合使用的完全缓解率为3/4。在基于镥的放射免疫疗法中加入培泊替尼后观察到DSB增加。在肾细胞癌和前列腺癌的临床前模型中，培泊替尼与基于镥的放射免疫疗法联合使用耐受性良好。我们的研究结果表明培泊替尼与基于镥的放射免疫疗法之间存在协同作用，其中培泊替尼增强了放射免疫疗法的疗效。这种协同作用表明有可能降低有效癌症治疗所需的放射免疫疗法剂量。
Zotero 插件