Foxton Caroline, Cornelissen Bart, O'Neill Edward, Waldron Bradley, Pretzmann Freja, Grønlund Rikke Veggerby, Hallund Mathias Wikke, Stevens Daniel J
Blue Earth Diagnostics Ltd., The Oxford Science Park, Magdalen Centre, Robert Robinson Avenue, Oxford, United Kingdom.
Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, United Kingdom.
Nucl Med Biol. 2025 Jul-Aug;146-147:109042. doi: 10.1016/j.nucmedbio.2025.109042. Epub 2025 Jun 8.
The prostate-specific membrane antigen (PSMA)-targeted radiohybrid ligand [Lu]Lu-rhPSMA-10.1 is a promising next-generation radiopharmaceutical therapy in prostate cancer. This preclinical evaluation comprised an in vitro screen of potential novel synergistic drug combinations with [Lu]Lu-rhPSMA-10.1, and an in vivo efficacy analysis of the lead drug combination in PSMA-expressing prostate cancer xenografts.
In total, 177 anticancer drugs were screened in a clonogenic survival assay of 22Rv1 cells which used 5-fold serial dilutions of the test drug (≤ 20 μM) to determine the half-maximal inhibitory concentration (IC), compared to incubations of the test drug plus [Lu]Lu-rhPSMA-10.1 (15 MBq) after 10 days. A subsequent focused screen assessed the impact of [Lu]Lu-rhPSMA-10.1 (0-25 MBq/mL) on drug IC. Synergy scores were determined using the zero interaction potency (ZIP) reference model (ZIP scores >5 % indicate high synergistic potency) and the multidimensional synergy of combinations (MuSyC) platform (log α >0 indicates synergistic potency). Therapeutic efficacy of the lead drug combination was evaluated in vivo: intravenous [Lu]Lu-rhPSMA-10.1 (30 MBq, single dose) and oral cobimetinib (0.25 mg/day for 21 days) (alone/in combination) were administered to 22Rv1 tumor-bearing NMRI nude mice (eight mice/group plus untreated controls). Tumor volume was measured twice weekly for 69 days (two-way ANOVA and Tukey's multiple comparisons test: data analyzed until three mice/group remained). KaplanMeier Log-rank survival analyses were performed.
In vitro screening identified cobimetinib (a mitogen-activated extracellular signal-regulated kinase inhibitor) as a lead candidate for synergistic combination with [Lu]Lu-rhPSMA-10.1 across a wide concentration range (ZIP score=13 %). MuSyC analysis suggested synergistic efficacy from enhanced potency of both drugs in the combination (both log α>3). Combination treatment significantly suppressed tumor growth in vivo versus untreated controls (from Day 13-30; p<0.01) and [Lu]Lu-rhPSMA-10.1 (from Day 17-30; p<0.001). Median survival was significantly longer with combination treatment (49 days) versus untreated controls (23 days; p=0.001) and [Lu]Lu-rhPSMA-10.1 monotherapy (36 days; p=0.002). No major compound-related toxicity for cobimetinib ± [Lu]Lu-rhPSMA-10.1 was observed.
The combination of cobimetinib and [Lu]Lu-rhPSMA-10.1 demonstrated enhanced preclinical therapeutic efficacy versus single agents, supporting clinical investigation of this novel drug combination in prostate cancer.
前列腺特异性膜抗原（PSMA）靶向放射性杂交配体[¹⁷⁷Lu]Lu-rhPSMA-10.1是一种有前景的前列腺癌下一代放射性药物疗法。该临床前评估包括对与[¹⁷⁷Lu]Lu-rhPSMA-10.1潜在的新型协同药物组合进行体外筛选，以及对先导药物组合在表达PSMA的前列腺癌异种移植模型中的体内疗效分析。
总共在22Rv1细胞的克隆形成存活试验中筛选了177种抗癌药物，该试验使用测试药物的5倍系列稀释液（≤20μM）来确定半数最大抑制浓度（IC），并与10天后测试药物加[¹⁷⁷Lu]Lu-rhPSMA-10.1（15MBq）的孵育结果进行比较。随后的重点筛选评估了[¹⁷⁷Lu]Lu-rhPSMA-10.1（0 - 25MBq/mL）对药物IC的影响。使用零相互作用效力（ZIP）参考模型（ZIP评分>5%表明高协同效力）和组合多维协同（MuSyC）平台（logα>0表明协同效力）确定协同分数。在体内评估先导药物组合的治疗效果：将静脉注射[¹⁷⁷Lu]Lu-rhPSMA-10.1（30MBq，单剂量）和口服考比替尼（0.25mg/天，共21天）（单独/联合）给予荷22Rv1肿瘤的NMRI裸鼠（每组8只小鼠加未治疗对照）。每周两次测量肿瘤体积，持续69天（双向方差分析和Tukey多重比较检验：分析数据直至每组剩余3只小鼠）。进行Kaplan-Meier对数秩生存分析。
体外筛选确定考比替尼（一种丝裂原活化的细胞外信号调节激酶抑制剂）是在广泛浓度范围内与[¹⁷⁷Lu]Lu-rhPSMA-10.1协同组合的主要候选药物（ZIP评分=13%）。MuSyC分析表明组合中两种药物效力增强产生协同疗效（两者logα>3）。联合治疗与未治疗对照相比在体内显著抑制肿瘤生长（从第13 - 30天；p<0.01）以及与[¹⁷⁷Lu]Lu-rhPSMA-10.1相比（从第17 - 30天；p<0.001）。联合治疗的中位生存期显著长于未治疗对照（49天）（23天；p=0.001）和[¹⁷⁷Lu]Lu-rhPSMA-10.1单药治疗（36天；p=0.002）。未观察到考比替尼±[¹⁷⁷Lu]Lu-rhPSMA-10.1的主要化合物相关毒性。
考比替尼与[¹⁷⁷Lu]Lu-rhPSMA-10.1的组合与单一药物相比显示出增强的临床前治疗效果，支持对这种新型药物组合在前列腺癌中的临床研究。
