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Investigation of IRS1/IRS2 inhibition in BCR-ABL1 cells using murine models

Grant number: 16/01639-3
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): September 01, 2016
Effective date (End): August 31, 2017
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Fabíola Traina
Grantee:Renata Scopim Ribeiro
Supervisor abroad: Brian Druker
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : Oregon Health & Science University, United States  
Associated to the scholarship:14/06037-6 - Investigation of IRS1/IRS2 silencing effects on the phenotype of CD34+ normal primary hematopoietic cells and BCR-ABL+ leukemic cells, BP.DR

Abstract

Chronic myeloid leukemia (CML) is a hematological malignancy associated with the BCR-ABL1 fusion gene, which drives the proliferative disease phenotype by activating multiple signaling pathways. Most CML patients are successfully treated with tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1. However, acquired drug resistance limits TKI efficacy in a significant subset of patients, warranting efforts to identify additional crucial proteins involved in BCR-ABL1 signaling pathways for further therapeutic intervention. We have previously identified IRS1 as a substrate of BCR-ABL1 in K562 cell line. Recently, a pharmacological IGF1R-IRS1/2 inhibitor (NT157) has been developed and has shown promising results in preclinical studies on solid tumors. The aim of this study is to investigate the anti-leukemic effects of IRS1 and IRS2 inhibition (lentivirus-mediated silencing and pharmacological inhibition with NT157) in murine cell lines expressing BCR-ABL1 and in mouse models of chronic myeloid leukemia induced by bone marrow transduction and transplantation or induced by BCR-ABL1 murine cell lines. Murine cells expressing or not BCR-ABL1 will be submitted to IRS1 or IRS2 lentivirus mediated silencing, or will be treated with the pharmacological IRS1/2 inhibitor NT157, and then submitted to evaluation of proliferation, apoptosis, and activation of PI3K/AKT and MAP kinase signaling. CML like disease will be induced in BALB/c mice by bone marrow transduction and transplantation or by BCR-ABL1 murine cell lines injection; mice will be treated with vehicle or NT157 and will be evaluated for survival and overall leukemia burden.