IGFBP7 and insulin/IGFs in childhood acute lymphoblastic leukemia chemoresistance

• Grant number: 12/03039-2
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): July 01, 2012
• Effective date (End): June 30, 2015
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: José Andrés Yunes
• Grantee: Angelo Brunelli Albertoni Laranjeira
• Home Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil

Abstract

Acute Lymphoblastic Leukemia (ALL) is the most common type of cancer in children. It is known that the interaction of leukemic blast cells with their microenvironment increases ALL resistance to chemotherapy. In recent work, we have shown the increased expression and secretion of IGFBP7 in leukemic cells after co-culture with bone marrow stroma cells. The 'leukemic' IGFBP7 together with IGF/insulin acts on stromal cells, inducing them to increase asparagine production, thus reducing the effect of L-asparaginase. Although the publication has been published in a high-impact, still misses to validate these findings in in vivo experiments. Furthermore, preliminary results, which are described in the present project, suggest that IGFBP7:insulin has a direct action on the ALL cells (anti-apoptotic) independent of stroma cells, in the resistance to other chemotherapeutic compounds. This, and the importance of the IGF system in progression, development and survival of different cell types and tumor, leads us to propose the continuation of the PhD project (FAPESP 08/02106-2). Therefore, this project aims to determine the role of IGFBP7 and the pathway of insulin/IGF in chemoresistance of ALL. Such experiments will be conducted with ALL strains, wild type or silenced (sh-RNA) for IR, IGF1R, or IGFBP7. Part of the project will be realized overseas to perform analyzes of the role of these pathways in ALL animal model. To confirm the main findings, with primary ALL cells, will be necessary to renew the scholarship for 12 months. We expect better describe the role of IGFBP7 and the insulin/IGF pathway in chemoresistance of ALL. The availability of drugs that act on the pathway of the insulin receptor (IR) and IGF1R, such as BMS-554417, are an additional incentive to this study and will be tested in vitro and in ALL animal models.