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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS

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Scholar  Download references 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. AUTHOR INFORMATION Author notes

* Rodrigo Esaki Tamura Present address: Department of Biological Sciences, Federal University of São Paulo, Diadema, SP, Brazil AUTHORS AND AFFILIATIONS * Viral Vector Laboratory, Center

for Translational Investigation in Oncology/LIM24, Cancer Institute of São Paulo, School of Medicine, University of São Paulo, SP, Brazil Rodrigo Esaki Tamura, Marlous G. Lana & Bryan E.

Strauss * Gene Therapy Laboratory, Department of Cell and Developmental Biology, Biomedical Sciences Institute, University of São Paulo, SP, Brazil Eugenia Costanzi-Strauss Authors *

Rodrigo Esaki Tamura View author publications You can also search for this author inPubMed Google Scholar * Marlous G. Lana View author publications You can also search for this author

inPubMed Google Scholar * Eugenia Costanzi-Strauss View author publications You can also search for this author inPubMed Google Scholar * Bryan E. Strauss View author publications You can

also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Bryan E. Strauss. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no

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SUPPLEMENTARY INFORMATION SUPPLEMENTAL MATERIAL RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Tamura, R.E., Lana, M.G., Costanzi-Strauss, E. _et al._

Combination of cabazitaxel and p53 gene therapy abolishes prostate carcinoma tumor growth. _Gene Ther_ 27, 15–26 (2020). https://doi.org/10.1038/s41434-019-0071-x Download citation *

Received: 05 December 2018 * Revised: 22 February 2019 * Accepted: 08 March 2019 * Published: 29 March 2019 * Issue Date: February 2020 * DOI: https://doi.org/10.1038/s41434-019-0071-x SHARE

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