Combination of cabazitaxel and p53 gene therapy abolishes prostate carcinoma tumor growth

Abstract

For patients with metastatic prostate cancer, the 5-year survival rate of 31% points to a need for novel therapies and improvement of existing modalities. We propose that p53 gene therapy and chemotherapy, when combined, will provide superior tumor cell killing for the treatment of prostate carcinoma. To this end, we have developed the AdRGD-PGp53 vector which offers autoregulated expression of p53, resulting in enhanced tumor cell killing in vitro and in vivo. Here, we combined AdRGD-PGp53 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 reveal that AdRGD-PGp53 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, AdRGD-PGp53 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 anti-tumor effects when combined with AdRGD-PGp53 in this mouse model. The AdRGD-PGp53 approach warrants further development for its application in gene therapy of prostate carcinoma.

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Acknowledgements

We thank Roger Chammas and his staff for ongoing support and critical discussions. We thank Otto Luiz Dutra Cerqueira for assistance during the preparation of this manuscript. This work was a collaborative effort with Sanofi-Aventis which facilitated the purchase of the cabazitaxel used here.

Funding

Financial support was received from the São Paulo Research Foundation, FAPESP (RET, 2011/21256–8; BES, 2013/25167–5 and 2015/26580–9) and from Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq (RET, 442738/2014–5; 302888/2017–9, BES). Financial support was provided by Sanofi-Aventis (ISS PRECLL 06945) in order to obtain the cabazitaxel used in this study.

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Correspondence to Bryan E. Strauss.

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