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Adenoviral vector-mediated mRTVP-1 gene therapy for prostate cancer
Takefumi Satoh1, Terry L Timme, Takashi Saika
1Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
We previously identified the mouse RTVP-1 (mRTVP-1; related to testes-specific, vespid, and pathogenesis proteins) gene as a direct target of p53 with proapoptotic activities in various cancer cell lines, including prostate cancer. To test the therapeutic potential of mRTVP-1 we constructed an adenoviral vector capable of efficient transduction and expression of mRTVP-1 (AdmRTVP-1) and used this vector in an orthotopic, metastatic mouse model of prostate cancer. A single intratumoral administration of AdmRTVP-1 gene therapy significantly reduced primary tumor wet weight compared with control Adbetagal-injected tumors at two time points after injection with two different vector doses (p < or = 0.01 at 7 and 14 days). Spontaneous metastasis to lung was also significantly reduced (p < or = 0.02). Evaluation of treated tumors revealed increased apoptosis and lower microvessel density counts. In a rat aortic ring sprouting assay, AdmRTVP-1 inhibited endothelial cell sprouting compared with Adbetagal, confirming its antiangiogenic activity. These therapeutic activities were associated with a significant increase in survival from 22.9 to 26.8 days (p = 0.003) in this aggressive model of prostate cancer. Interestingly, there were significant increases in the infiltration of tumor-associated macrophages, dendritic cells, and CD8+ T cells, which persisted at 14 days posttreatment in the AdmRTVP-1-treated tumors compared with Adbetagal control-treated tumors. In addition, significantly increased natural killer and cytotoxic T lymphocyte activities were demonstrated in the mice with AdmRTVP-1-treated tumors. The unique therapeutic properties of AdmRTVP-1 gene therapy demonstrated in this study provide new opportunities for gene and immunotherapy of prostate cancer and potentially other malignancies.
Insights
Gene therapy using mouse RTVP-1 (mRTVP-1) significantly reduced prostate cancer growth, metastasis, and improved survival in mice. AdmRTVP-1 also demonstrated antiangiogenic effects and boosted anti-tumor immune responses.
Area of Science:
- Oncology
- Gene Therapy
- Immunotherapy
Background:
- Mouse RTVP-1 (mRTVP-1) is a p53 target gene with proapoptotic functions.
- mRTVP-1 has shown activity in various cancer cell lines, including prostate cancer.
Purpose of the Study:
- To evaluate the therapeutic potential of mRTVP-1 gene therapy in an aggressive, metastatic mouse model of prostate cancer.
- To assess the antiangiogenic and immunomodulatory effects of AdmRTVP-1.
Main Methods:
- Construction of an adenoviral vector for mRTVP-1 expression (AdmRTVP-1).
- Administration of AdmRTVP-1 via intratumoral injection in an orthotopic prostate cancer mouse model.
- Assessment of tumor growth, metastasis, apoptosis, microvessel density, and immune cell infiltration.
Main Results:
- AdmRTVP-1 significantly reduced primary tumor weight and lung metastasis.
- Treated tumors showed increased apoptosis and decreased microvessel density, indicating antiangiogenic activity.
- AdmRTVP-1 therapy enhanced infiltration of immune cells (macrophages, dendritic cells, CD8+ T cells) and boosted natural killer and cytotoxic T lymphocyte activities, improving survival.
Conclusions:
- AdmRTVP-1 gene therapy exhibits significant anti-tumor efficacy and immunomodulatory effects in prostate cancer.
- This approach offers a promising strategy for prostate cancer treatment and potentially other malignancies.
- The study highlights the potential of combining gene therapy with immunotherapy for enhanced anti-cancer outcomes.