Abstract B17: Gene therapy and chemotherapy cooperate to inhibit prostate cancer progression in an animal model

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Abstract Patients with localized prostate carcinoma have a 5 year-survival rate of almost 100%; however, for patients with metastatic disease the rate is 31%, and mortality in 90% of these cases is the result of metastases. Clearly, there is a need for novel therapies and room for improving existing modalities. We propose that gene therapy and chemotherapy, when combined, may provide superior tumor cell killing. Our laboratory has developed a novel adenoviral vector expressing p53 under the control of a p53 responsive promoter; thus a positive feedback mechanism is established, providing high levels of p53, resulting in cell death of prostate cancer cells in vitro and in vivo. In previous assays, we have shown that our vector (AdRGDPGp53) is more effective than typical gene therapy approaches which employ a constitutive promoter (CMV) to control expression of p53. Here, we evaluate whether the union of gene therapy and chemotherapy applied to prostate cancer cell lines would promote a synergistic response in the induction of programmed cell death and reduction of tumor progression in an animal model. We combined AdRGDPGp53 along with the chemotherapy drugs used in the clinical treatment of prostate carcinoma, mitoxantrone, docetaxel, or cabazitaxel. Our results indicate that all drugs increase phosphorylation of p53, leading to improved induction of p53 targets. In vitro experiments indicate that AdRGDPGp53 sensitizes prostate cancer cells to each of the drugs tested, conferring increased levels of cell death. In a xenograft mouse model of in situ gene therapy, AdRGDPGp53 treatment, when combined with cabazitaxel, drastically reduced tumor progression and increased survival rates to 100%. Strikingly, we used a sub-therapeutic dose of cabazitaxel, thus avoiding leukopenia, yet still showed potent antitumor effects when combined with AdRGDPGp53 in this mouse model. The AdRGDPGp53 approach warrants further development for its application in gene therapy of prostate carcinoma. Citation Format: Rodrigo Esaki Tamura, Bryan Eric Strauss. Gene therapy and chemotherapy cooperate to inhibit prostate cancer progression in an animal model [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B17.