Ahmanson Translational Theranostic Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), CA, USA.
Department of Translational Medicine, Division of Urological Cancers, Skåne University Hospital Malmö, Lund University, Sweden.
Theranostics. 2020 Feb 3;10(6):2612-2620. doi: 10.7150/thno.42228. eCollection 2020.
Ac-PSMA-617 targeted-therapy has demonstrated efficacy in 75-85% of patients; however, responses are not durable. We aimed to establish translatable mouse models of disseminated prostate cancer (PCa) to evaluate effectiveness of Ac-PSMA-617 at various disease stages. : C4-2, C4-2B, or 22Rv1 cells were injected into the left ventricle of male NSG mice. Disease progression was monitored using bioluminescence imaging (BLI). For treatment, mice were injected with 40 kBq Ac-PSMA-617 at one (early treatment cohort) or three weeks (late treatment cohort) post-inoculation. Treatment efficacy was monitored by BLI of whole-body tumor burden. Mice were sacrificed based on body conditioning score. : C4-2 cells yielded metastases in liver, lungs, spleen, stomach, bones, and brain - achieving a clinically relevant model of widespread metastatic disease. The disease burden in the early treatment cohort was stable over 27 weeks in 5/9 mice and progressive in 4/9 mice. These mice were sacrificed due to brain metastases. Median survival of the late treatment cohort was superior to controls (13 vs. 7 weeks; p<0.0001) but inferior to that in the early treatment cohort (13 vs. 27 weeks; p<0.001). Late cohort mice succumbed to extensive liver involvement. The 22Rv1 and C4-2B systemic models were not used for treatment due to high kidney metastatic burden or low take rate, respectively. : C4-2 cells reproduced metastatic cancer spread most relevantly. Early treatment with Ac-PSMA-617 prevented liver metastases and led to significant survival benefit. Late treatment improved survival without reducing tumor burden in the liver, the main site of metastasis. The current findings suggest that early Ac-PSMA-617 intervention is more efficacious in the setting of widespread metastatic PCa.
阿霉素-PSMA-617 靶向治疗在 75-85%的患者中显示出疗效；然而，反应并不持久。我们旨在建立可传播的前列腺癌（PCa）小鼠模型，以评估阿霉素-PSMA-617 在各种疾病阶段的有效性。将 C4-2、C4-2B 或 22Rv1 细胞注入雄性 NSG 小鼠的左心室。使用生物发光成像（BLI）监测疾病进展。对于治疗，在接种后一周（早期治疗队列）或三周（晚期治疗队列），向小鼠注射 40 kBq 阿霉素-PSMA-617。通过 BLI 监测全身肿瘤负担来监测治疗效果。根据身体状况评分，处死小鼠。C4-2 细胞在肝脏、肺部、脾脏、胃、骨骼和大脑中产生转移，实现了广泛转移性疾病的临床相关模型。在早期治疗队列中，5/9 只小鼠的疾病负担在 27 周内保持稳定，4/9 只小鼠的疾病负担呈进展性。这些小鼠因脑转移而被处死。晚期治疗队列的中位生存期优于对照组（13 与 7 周；p<0.0001），但劣于早期治疗队列（13 与 27 周；p<0.001）。晚期队列的小鼠因广泛的肝受累而死亡。由于肾转移负担高或摄取率低，分别未使用 22Rv1 和 C4-2B 系统模型进行治疗。C4-2 细胞最相关地再现了转移性癌症的扩散。早期使用阿霉素-PSMA-617 治疗可预防肝转移并导致显著的生存获益。晚期治疗改善了生存，但未降低肝脏（主要转移部位）的肿瘤负担。目前的研究结果表明，在广泛转移性 PCa 中，早期阿霉素-PSMA-617 干预更有效。
