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Combination of chemotherapy and adenoviral vectors expressing p53 for the therapy of prostate cancer

Grant number: 11/21256-8
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): June 01, 2012
Effective date (End): May 31, 2015
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Bryan Eric Strauss
Grantee:Rodrigo Esaki Tamura
Host Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil


Prostate cancer accounts for 28% of new cases of cancer and is second in mortality due to cancer in men. Patients who develop only localized tumor have a 5 year-survival rate of almost 100%, however, for patients with metastatic prostate cancer the rate is 31%, and mortality in 90% of cases is the result of systemic dissemination and metastasis. In this project we aim to combine traditional chemotherapy used in the clinic with new viral vectors developed in the Viral Vector Laboratory, São Paulo State Cancer Institute (ICESP) and to evaluate whether the union of different strategies applied to prostate cancer cell lines promotes a synergistic response in the induction of programmed cell death and reduction of tumor progression in an animal model. To this end, we have developed non-replicating adenoviral vectors encoding p53 where expression of this cDNA is controlled by a promoter containing p53-responsive elements, thus establishing a positive feedback mechanism, which should provide greater p53 expression as compared with adenoviral vectors that utilize the constitutive CMV promoter. A second improvement to the adenoviral vector was the modification of the fiber protein with the insertion of the RGD tripeptide, permitting the transduction of target cells, even in the absence of the adenoviral receptor (CAR). Along with these vectors, we plan to apply the chemotherapy drugs Docetaxel, Cabazitaxel and Mitoxantrone with the expectation of increasing cell death. Upon confirmation of the response in vitro and in vivo, one potential perspective of this work would be to extend this study to test prostate cancer cells from patients and evaluate the clinical relevance of this combination therapy.

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Scientific publications (5)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
TAMURA, RODRIGO ESAKI; DE LUNA, IGOR VIEIRA; LANA, MARLOUS GOMES; STRAUSS, BRYAN E.. Improving adenoviral vectors and strategies for prostate cancer gene therapy. Clinics, v. 73, n. 1, . (11/21256-8, 15/26580-9, 12/05066-7, 16/18197-3, 13/25167-5)
DA-COSTA, R. C.; VIEIRA, I. L.; HUNGER, A.; TAMURA, R. E.; STRAUSS, B. E.. p19Arf sensitizes B16 melanoma cells to interferon-beta delivered via mesenchymal stem cells in vitro. Brazilian Journal of Medical and Biological Research, v. 53, n. 3, . (13/25167-5, 11/10656-5, 16/18197-3, 11/21256-8, 15/26580-9)
TAMURA, RODRIGO ESAKI; DA SILVA SOARES, RAFAEL BENTO; COSTANZI-STRAUSS, EUGENIA; STRAUSS, BRYAN E.. Autoregulated expression of p53 from an adenoviral vector confers superior tumor inhibition in a model of prostate carcinoma gene therapy. CANCER BIOLOGY & THERAPY, v. 17, n. 12, p. 1221-1230, . (11/21256-8, 13/25167-5)
VIEIRA, IGOR DE LUNA; TAMURA, RODRIGO ESAKI; HUNGER, ALINE; STRAUSS, BRYAN E.. Distinct Roles of Direct Transduction Versus Exposure to the Tumor Secretome on Murine Endothelial Cells After Melanoma Gene Therapy with Interferon-beta and p19Arf. JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, v. 39, n. 4, p. 246-258, . (13/25167-5, 11/10656-5, 11/21256-8, 15/26580-9)
TAMURA, RODRIGO ESAKI; HUNGER, ALINE; FERNANDES, DENISE C.; LAURINDO, FRANCISCO R.; COSTANZI-STRAUSS, EUGENIA; STRAUSS, BRYAN E.. Induction of Oxidants Distinguishes Susceptibility of Prostate Carcinoma Cell Lines to p53 Gene Transfer Mediated by an Improved Adenoviral Vector. Human Gene Therapy, v. 28, n. 8, p. 639-653, . (11/21256-8, 13/25167-5)

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