A novel synergistic drug combination of a mitogen-activated extracellular signal-regulated kinase inhibitor with [177Lu]Lu-rhPSMA-10.1 for prostate cancer treatment: Results of a preclinical evaluation

IF 3.6 4区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Nuclear medicine and biology Pub Date : 2025-06-08 DOI:10.1016/j.nucmedbio.2025.109042

Caroline Foxton , Bart Cornelissen , Edward O'Neill , Bradley Waldron , Freja Pretzmann , Rikke Veggerby Grønlund , Mathias Wikke Hallund , Daniel J. Stevens

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引用次数: 0

Abstract

Purpose

The prostate-specific membrane antigen (PSMA)-targeted radiohybrid ligand [¹⁷⁷Lu]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 [¹⁷⁷Lu]Lu-rhPSMA-10.1, and an in vivo efficacy analysis of the lead drug combination in PSMA-expressing prostate cancer xenografts.

Methods

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 (IC₅₀), compared to incubations of the test drug plus [¹⁷⁷Lu]Lu-rhPSMA-10.1 (15 MBq) after 10 days. A subsequent focused screen assessed the impact of [¹⁷⁷Lu]Lu-rhPSMA-10.1 (0–25 MBq/mL) on drug IC₅₀. 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 [¹⁷⁷Lu]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.

Results

In vitro screening identified cobimetinib (a mitogen-activated extracellular signal-regulated kinase inhibitor) as a lead candidate for synergistic combination with [¹⁷⁷Lu]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 [¹⁷⁷Lu]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 [¹⁷⁷Lu]Lu-rhPSMA-10.1 monotherapy (36 days; p=0.002). No major compound-related toxicity for cobimetinib ± [¹⁷⁷Lu]Lu-rhPSMA-10.1 was observed.

Conclusions

The combination of cobimetinib and [¹⁷⁷Lu]Lu-rhPSMA-10.1 demonstrated enhanced preclinical therapeutic efficacy versus single agents, supporting clinical investigation of this novel drug combination in prostate cancer.

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有丝分裂原激活的细胞外信号调节激酶抑制剂与[177Lu]Lu-rhPSMA-10.1联合治疗前列腺癌：临床前评估结果

目的前列腺特异性膜抗原（PSMA）靶向放射杂交配体[177Lu]Lu-rhPSMA-10.1是治疗前列腺癌的新一代放射药物。这项临床前评估包括与[177Lu]Lu-rhPSMA-10.1的潜在新型协同药物组合的体外筛选，以及对表达psma的前列腺癌异种移植物中先导药物组合的体内疗效分析。方法在22Rv1细胞克隆生存实验中，筛选177种抗癌药物，用5倍连续稀释试验药物（≤20 μM）测定半最大抑制浓度（IC50），并与试验药物加[177Lu]Lu-rhPSMA-10.1 （15 MBq）孵育10天后进行比较。随后的重点筛选评估了[177Lu]Lu-rhPSMA-10.1 （0-25 MBq/mL）对药物IC50的影响。协同得分采用零交互效力（ZIP）参考模型（ZIP分数>； 5%表示高协同效力）和多维组合协同（MuSyC）平台（log α >；0表示协同效力）确定。在体内评估联合用药的治疗效果：静脉注射[177Lu]Lu-rhPSMA-10.1 （30 MBq，单剂量）和口服cobimetinib （0.25 mg/天，连续21天）（单独/联合）给药22只rv1荷瘤NMRI裸鼠（8只/组+未治疗对照组）。每周测量两次肿瘤体积，持续69天（双向方差分析和Tukey多重比较检验：分析数据，直到3只小鼠/组）。进行kaplan - meier Log-rank生存分析。结果体外筛选发现，cobimetinib（一种丝裂原激活的胞外信号调节激酶抑制剂）与[177Lu]Lu-rhPSMA-10.1在较宽的浓度范围内协同作用（ZIP评分= 13%）。MuSyC分析表明，两种药物联合使用时效力增强，具有协同作用（均为log α>；3）。与未治疗对照组相比，联合治疗显著抑制肿瘤生长(从第13-30天；p<0.01)和[177Lu]Lu-rhPSMA-10.1(从第17-30天；术中,0.001)。联合治疗的中位生存期（49天）明显长于未治疗的对照组(23天；p=0.001)和[177Lu]Lu-rhPSMA-10.1单药治疗(36天；p = 0.002)。未观察到cobimetinib±[177Lu]Lu-rhPSMA-10.1的主要化合物相关毒性。结论与单药相比，cobimetinib与[177Lu]Lu-rhPSMA-10.1联用治疗前列腺癌的临床前疗效明显增强，支持该新型药物联用治疗前列腺癌的临床研究。

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来源期刊

Nuclear medicine and biology 医学-核医学

CiteScore

6.00

自引率

9.70%

发文量

479

审稿时长

51 days

期刊介绍： Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized. These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field. Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.