Development of high capacity adenoviral system expressing antitumoral genes

• Grant number: 19/15619-2
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: December 01, 2019
• End date: November 30, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Rodrigo Esaki Tamura
• Grantee: Rodrigo Esaki Tamura
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
• Associated researchers: Cristina Viana Niero ; Ileana Gabriela Sánchez de Rubió ; João Henrique Ghilardi Lago ; Julio Cezar Franco de Oliveira
• Associated scholarship(s): 24/02802-1 - Cloning cyclodipeptide synthases of Nocardiopsis prasina in eukaryotic expression vector for evaluation of antitumor activity, BP.IC; 23/11322-0 - Development of a high-capacity adenoviral system expressing the Azurin gene and evaluation of antitumor activity, BP.MS; 23/03195-9 - Development of high capacity adenovirus vectors with different therapeutical approaches for cancer treatment, BP.DD; + associated scholarships 23/01291-0 - Evaluation of the antitumor activity of Azurin by crotamine-mediated gene transfer in melanoma cells., BP.IC; 23/02034-1 - Study of the ability of drugs to inhibit the NSP3-mediated lung proinflammatory response of SARS-CoV-2 through modulation of the STAT3 pathway, BP.IC; 22/14015-9 - Identification of bacterial products with antitumor activity in a bacterial library obtained from compost material from the São Paulo Zoo, BP.IC; 21/03418-2 - High capacity adenoviral vetor development expressing HSVtk and IL-12 expression cassette optimized under control of calcitonin promoter, BP.MS; 21/02659-6 - Development of High capacity adenoviral system emplying Ad-HD and helper of distantly related serotypes, BP.MS; 20/08271-7 - Development of high capacity adenoviral system expressing antitumoral genes, BP.JP - associated scholarships

Abstract

Gene therapy through viral vectors has great potential, already being used in clinical protocols in humans. Third-generation adenoviral vectors (high capacity, gutless, or helper-dependent-HD) are safer than first-generation vectors and have increased gene insertion capacity; however, its the main limitation for large-scale application is to obtain virus particles free of contamination by the helper virus. Adenoviruses from phylogenetically close serotypes have cross-packaging capacity, but phylogenetically distant viruses do not. Thus, we will develop a high capacity adenoviral system in which the gutless and the helper vectors are phylogenetically distant, preventing the packaging of the helper vector and its presence as a contaminant in the Ad-HD preparation. Eliminating contamination by the helper virus has a great potential to increase the employment of high capacity adenoviral vectors. We intend to employ adenoviral vectors as vehicles for the transfer of genes with antitumor activity. Strategies for expression of suicide gene allied to the immunomodulatory gene with conditional expression and production of bacterial toxins will be employed. The Herpes Simplex virus thymidine kinase (HSVtk) and Interleukin-12 (IL-12) genes are very well described and are a good model for initiating these studies. We intend to clone the HSVtk and optimized IL-12 genes into adenoviral vector with calcitonin responsive promoter and to evaluate its activity on medullary thyroid carcinoma cells. Another gene that will be evaluated is the Azurin gene, which has selective activity only on tumor cells. Therefore, we will evaluate the ability of these vectors to induce death of tumor cells in vitro and in vivo. We are currently investigating a large bacterial library for the ability to produce products, that are capable of inhibiting the viability of prostate cancer cells, thus providing the prospect of identifying new bacterial genes with antitumor activity. (AU)

Scientific publications

(8)

(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)

SIMABUCO, FERNANDO MOREIRA; TAMURA, RODRIGO ESAKI; BETIM PAVAN, ISADORA CAROLINA; MORALE, MIRIAN GALLIOTE; VENTURA, ARMANDO MORAIS. Molecular mechanisms and pharmacological interventions in the replication cycle of human coronaviruses. GENETICS AND MOLECULAR BIOLOGY, v. 44, n. 1, 1, 2021. (19/15619-2, 16/25139-0, 18/08391-2, 18/14818-9, 20/05346-6)

MORALE, MIRIAN GALLIOTE; TAMURA, RODRIGO ESAKI; SANCHEZ RUBIO, ILEANA GABRIELA. Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models. BIOMOLECULES, v. 12, n. 3, p. 18-pg., 2022-03-01. (16/25139-0, 19/15619-2, 20/08271-7)

SIMABUCO, FERNANDO MOREIRA; TAMURA, RODRIGO ESAKI; BETIM PAVAN, ISADORA CAROLINA; MORALE, MIRIAN GALLIOTE; VENTURA, ARMANDO MORAIS. Molecular mechanisms and pharmacological interventions in the replication cycle of human coronaviruses. GENETICS AND MOLECULAR BIOLOGY, v. 44, n. 1, p. 18-pg., 2021-01-01. (16/25139-0, 19/15619-2, 18/14818-9, 20/05346-6, 18/08391-2)

TAMURA, RODRIGO ESAKI; SAID, SAID MUHAMMAD; DE FREITAS, LETICIA MUSSIN; SANCHEZ RUBIO, ILEANA GABRIELA. Outcome and death risk of diabetes patients with Covid-19 receiving pre-hospital and in-hospital metformin therapies. DIABETOLOGY & METABOLIC SYNDROME, v. 13, n. 1, JUL 13 2021. (20/08271-7, 19/15619-2)

MORALE, MIRIAN GALLIOTE; TAMURA, RODRIGO ESAKI; CINTRA, RICARDO; ARAUJO, NATALIA MENESES; VILLA, LUISA LINA. TLR4 and SARM1 modulate survival and chemoresistance in an HPV-positive cervical cancer cell line. SCIENTIFIC REPORTS, v. 12, n. 1, p. 12-pg., 2022-04-25. (16/25139-0, 19/15619-2, 08/57889-1, 08/03232-1)

MACHADO, RANYELISON S.; TRISTAO, DANIELA C.; ARAUJO, NATALIA M.; SEIF, ELIAS JORGE MUNIZ; DA CRUZ, KAYO ALEXANDRE S.; MORALE, MIRIAN G.; DE RUBIO, ILEANA GABRIELA S.; LAGO, JOAO HENRIQUE G.; TAMURA, RODRIGO E.. Dicentrine and its N-oxide derivatives induces apoptotic and necrotic cell death in prostate cancer cell lines. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY REPORTS, v. 13, p. 15-pg., 2025-03-03. (23/03195-9, 21/02789-7, 23/02690-6, 20/08271-7, 19/15619-2, 23/12447-1, 21/03418-2, 23/11322-0)

RODRIGUES, MARIANA TEIXEIRA; MICHELLI, ANA PAULA PICARO; CASO, GUSTAVO FELISOLA; DE OLIVEIRA, PALOMA RAMOS; RODRIGUES-JUNIOR, DORIVAL MENDES; MORALE, MIRIAN GALLIOTE; MACHADO JUNIOR, JOEL; BORTOLUCI, KARINA RAMALHO; TAMURA, RODRIGO ESAKI; DA SILVA, TAMIRIS REISSA CIPRIANO; et al. Lysicamine Reduces Protein Kinase B (AKT) Activation and Promotes Necrosis in Anaplastic Thyroid Cancer. PHARMACEUTICALS, v. 16, n. 12, p. 18-pg., 2023-12-01. (14/24549-4, 23/02690-6, 19/15619-2)

NATÁLIA MENESES ARAÚJO; ILEANA GABRIELA SANCHEZ RUBIO; NICHOLAS PIETRO AGULHA TONETO; MIRIAN GALLIOTE MORALE; RODRIGO ESAKI TAMURA. The use of adenoviral vectors in gene therapy and vaccine approaches. GENETICS AND MOLECULAR BIOLOGY, v. 45, n. 3, 2022-10-07. (20/08271-7, 21/03418-2, 21/02659-6, 19/15619-2)