| Grant number: | 13/25167-5 |
| Support Opportunities: | Regular Research Grants |
| Start date: | April 01, 2014 |
| End date: | June 30, 2016 |
| Field of knowledge: | Biological Sciences - Biochemistry - Molecular Biology |
| Principal Investigator: | Bryan Eric Strauss |
| Grantee: | Bryan Eric Strauss |
| 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 |
Abstract
Melanoma is an especially difficult tumor to treat once it has metastasized. Traditional approaches, such as chemotherapy with dacarbazine, are limited in their efficacy while newer drugs, such as vemurafanib (B-Raf inhibitor), are associated with acquired resistance to therapy. However, since 90% of melanomas retain wild-type p53, we propose this genotype may provide advantages that favor the development of novel treatments, such as gene therapy. To this end, the Viral Vector Laboratory (Cancer Institute of Sao Paulo-ICESP) has developed a series of gene transfer platforms that offer transgene expression under the control of a p53-responsive promoter. When used to deliver p19Arf (tumor suppressor protein, functional partner of p53) as well as interferon-beta (IFN², an immune modulatory cytokine with anti-tumor properties), we observed, in vitro and in vivo, that the combination, but not individual gene transfer, was associated with enhanced killing of B16 mouse melanoma cells (p53 wild-type). However, additional assays are required in order to delineate the impact of this combination as compared to the transfer of p19Arf or IFN² alone. We propose to explore this point first by exploring whether the combined treatment induces bona fide immunogenic cell death, indicated by the liberation of calreticulin, ATP and HMGB1. Assays will also be performed using either chemical inducers of IFN² or recombinant IFN² protein in order to better define the role of endogenous versus exogenous IFN² for the induction of cell death in the presence of p19Arf. The activation of endogenous p53 by Nutlin-3, an activator of p53 and antagonist of MDM2, will be employed in combination with IFN² treatment (gene transfer or recombinant protein) in order reveal the limitations of the pharmacological approach. We will also explore whether gene transfer of p19Arf and IFN² in vivo may induce an anti-tumor response that confers an immunologic protection against the formation of secondary tumors. With the success of this project, we hope to show that our gene transfer approach combining p19Arf and IFN² is superior to the mono-treatment in several key aspects. (AU)
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