IP: Dr. Ramón Mangues Bafalluy

Resumen del proyecto: The HTLV-1 virus is the etiologic agent in the T cell leukemia/lymphoma of the adult (ATL), a very aggressive neoplasia which does not respond to conventional chemotherapy. It is estimated that 15-20 million people are carriers of HTLV-1 worldwide, being the main endemic areas the southeast of Japan, South America, Equatorial Africa and the Caribbean. In Brazil one of the countries with higher prevalence in South America, the number of carriers is 2.5 million. ATL is developed in 2-5% of virus carriers; however, the cause and determinants for the different clinical forms of ATL are unknown. Focal adhesions are protein complexes which after their activation by different receptors activate survival pathways and inhibit cell death. Different focal adhesion proteins are activated by HTLV-1 infection in the ATL cells, which indicate that this signaling pathway could be involved in the pathogenesis by HTLV-1. In this project, we aim at performing an exhaustive study of the molecular alterations present in 50 samples of ATL patients and its comparison with 50 samples from asymptomatic carriers of HTLV-1, with the goal of evaluating the pathways involved in the oncogenesis by HTLV-1.This study will assess the cell death and signaling pathways in which focal adhesions are involved in ATL cells, as compared to normal lymphocytes. Moreover, since current ATL therapy is scarcely effective, especially in the acute and lymphomatous subtypes, we will evaluate the antitumor effect and mechanism of action, both in vitro e in vivo, of a new inhibitor of focal adhesion signaling. This compound has demonstrated antitumor activity in different hematologic neoplasias. To evaluate the antitumor activity of E7123 in vivo, we will establish an animal model in NOG mice, using ATL cell lines labeled with bioluminescence which will allow the in vivo follow-up of their migration and implantation as well as the evaluation of antitumor effect after E7123 administration.

Entidad financiadora: Conselho Nacional de Desenvolvimiento Científico e Tecnológico de Brasil