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

• Grant number: 16/01639-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: September 01, 2016
• End date: August 31, 2017
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Fabíola Traina
• Grantee: Renata Scopim Ribeiro
• Supervisor: Brian Druker
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: 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.

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)

SCOPIM-RIBEIRO, RENATA; MACHADO-NETO, JOAO AGOSTINHO; EIDE, CHRISTOPHER A.; COELHO-SILVA, JUAN LUIZ; FENERICH, BRUNA ALVES; FERNANDES, JAQUELINE CRISTINA; SCHEUCHER, PRISCILA SANTOS; STEVENS, SAMANTHA L. SAVAGE; CAMPOS, PAULA DE MELO; OLALLA SAAD, SARA T.; et al. NT157, an IGF1R-IRS1/2 inhibitor, exhibits antineoplastic effects in pre-clinical models of chronic myeloid leukemia. INVESTIGATIONAL NEW DRUGS, v. 39, n. 3, JAN 2021. (14/06037-6, 13/08135-2, 16/01639-3)