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Updated: Dec 25, 2025
Pre-clinical Orthotopic Murine Model of Human Prostate Cancer
Published on: August 29, 2016
Targeted alpha therapy in a systemic mouse model of prostate cancer - a feasibility study
Andreea D Stuparu1, Catherine A L Meyer1, Susan L Evans-Axelsson2
1Ahmanson Translational Theranostic Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), CA, USA.
Abstract:
225Ac-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 225Ac-PSMA-617 at various disease stages. Methods: 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 225Ac-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. Results: 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. Conclusion: C4-2 cells reproduced metastatic cancer spread most relevantly. Early treatment with 225Ac-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 225Ac-PSMA-617 intervention is more efficacious in the setting of widespread metastatic PCa.
Insights
Early administration of actinium-225 prostate-specific membrane antigen targeted therapy (225Ac-PSMA-617) significantly improves survival in metastatic prostate cancer (PCa) mouse models. This study highlights the critical timing for effective 225Ac-PSMA-617 intervention in advanced PCa.
Area of Science:
- Oncology
- Radiopharmaceutical Therapy
- Preclinical Cancer Models
Background:
- Actinium-225 prostate-specific membrane antigen targeted therapy (225Ac-PSMA-617) shows high initial efficacy in prostate cancer (PCa) patients.
- Treatment responses to 225Ac-PSMA-617 are often not durable, necessitating further investigation into optimal treatment timing.
- Development of translatable preclinical models is crucial for evaluating therapeutic strategies at various disease stages.
Purpose of the Study:
- To establish clinically relevant mouse models of disseminated prostate cancer (PCa).
- To evaluate the effectiveness of 225Ac-PSMA-617 in these models at early versus late disease stages.
- To determine the impact of treatment timing on survival and metastatic burden.
Main Methods:
- C4-2, C4-2B, or 22Rv1 prostate cancer cells were injected into the left ventricle of NSG mice to establish disseminated disease.
- Disease progression was monitored using bioluminescence imaging (BLI).
- Mice received 40 kBq 225Ac-PSMA-617 at either one week (early) or three weeks (late) post-inoculation; control groups were untreated.
Main Results:
- The C4-2 cell line successfully generated widespread metastases, creating a clinically relevant model of disseminated PCa.
- Early treatment with 225Ac-PSMA-617 stabilized disease in 5/9 mice over 27 weeks and prevented liver metastases.
- Late treatment significantly improved median survival compared to controls (13 vs. 7 weeks, p<0.0001) but was less effective than early treatment (13 vs. 27 weeks, p<0.001), with mice succumbing to extensive liver involvement.
Conclusions:
- The C4-2 cell line provides a robust model for studying widespread metastatic prostate cancer.
- Early intervention with 225Ac-PSMA-617 demonstrates superior efficacy, preventing key metastases and offering a substantial survival benefit.
- These findings underscore the importance of initiating 225Ac-PSMA-617 treatment at an earlier stage for maximum benefit in metastatic PCa.
