P53/ARF and interferon-beta pathways as targets for colorectal carcinoma gene therapy

• Grant number: 13/16074-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): November 01, 2013
• Effective date (End): July 31, 2018
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Bryan Eric Strauss
• Grantee: Paulo Roberto Del Valle
• 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
• Associated scholarship(s): 16/04446-1 - Quinacrine and 5-fluorouracil treatment of primary colorectal tumor samples, BE.EP.DR

Abstract

Colorectal cancer is the third in mortality and, despite the molecular classifications, between 30% and 40% of patients relapse after chemotherapy, which indicates the need for new therapeutic strategies. There is a growing number of studies using viral vectors for cancer gene therapy, and data from our laboratory has shown that the combined delivery of Arf (tumor suppressor) and interferon-beta (IFNb, immunomodulatory cytokine) genes via adenoviral vectors under control of a p53 responsive promoter caused massive cell death and an important immunomodulatory effect. However, these results were observed in mice. This study will evaluate whether the effect observed with this combination of gene transfer is repeated in a human carcinoma model using the cell line HCT116 (human colorectal carcinoma, p53-wild type) in vitro and in vivo. We also intend to assess the role of p53 in this response through the use of isogenic cell line, HCT116p53-/ -, where the endogenous p53 was knocked out. Also, we will set up an ex vivo model to evaluate dendritic cell (main immune response guider) and T cell responsiveness from cancer patients and healthy donors when co-cultured with cell lines treated with our viral vectors. With this project, our approach in gene therapy will be evaluated in a human model that will reveal not only the response to the transgenes, but also opens the way to study the role of p53 in our treatments and evaluates whether this treatment can activate an immune response in the human model.

Scientific publications

(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)

STRAUSS, BRYAN E.; OLIVEIRA SILVA, GISSELE ROLEMBERG; VIEIRA, IGOR DE LUNA; DUTRA CERQUEIRA, OTTO LUIZ; DEL VALLE, PAULO ROBERTO; VIEIRA MEDRANO, RUAN FELIPE; MENDONCA, SAMIR ANDRADE. Perspectives for cancer immunotherapy mediated by p19Arf plus interferon-beta gene transfer. Clinics, v. 73, n. 1, 2018. (12/05066-7, 16/18197-3, 13/09474-5, 13/25167-5, 13/16074-3, 15/26580-9)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

VALLE, Paulo Roberto Del. P53/Arf and interferon beta pathways as colorectal cancer gene therapy targets. 2018. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) São Paulo.