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Investigation of mutations in IGF1R/IRS pathway in Myeloproliferative Neoplasm and the effect of pharmacological inhibitors of this signaling pathway in JAK2V617F knockin murine model

Grant number: 16/14049-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): January 01, 2018
Effective date (End): April 30, 2021
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Fabíola Traina
Grantee:Jaqueline Cristina Fernandes
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

JAK2, MPL and CALR mutations activate the JAK/STAT pathway, confer cellular proliferation independent of growth factors and contribute to the pathogenesis of Myeloproliferative Neoplasms (MPN). Ruxolitinib is a selective inhibitor for JAK1/JAK2 approved for the treatment of Primary Myelofibrosis. However, the lack of efficiency in inducing complete remission in patients with MPN indicates the need to identify new therapeutic strategies for these diseases. A previous study conducted by our research group identified an involvement of the Insulin Receptor Substrate 2 (IRS2) in the pathogenesis of MPN and indicated that the IGF1R/IRS pharmacological inhibitor, NT157, inhibits the viability of primary patients with JAK2 V617F positive MPN. An independent research group has recently indicated an involvement of IGF1R in the pathogenesis of MPN, corroborating the data and providing new evidence of the involvement of IGF1R/IRS in this pathology. The aim of this work is to investigate the molecular and transnational mechanisms of the IGF1R/IRS participation in MPN pathophysiology. Mutations in genes encoding proteins of the IGF1R/IRS signaling pathway will be investigated, by second generation sequencing, in DNA samples collected at diagnosis from a cohort of MPN patients from our institution. Selective IGF1R/IR (OSI-906) and IGF1R/IRS (NT157) pharmacological inhibitors will be tested in JAK2V617F knockin murine model; animals will be submitted to analysis of tumor burden and survival. The in vitro and in vivo effects of these pharmacological inhibitors in the activation of signaling pathways and in the survival of BaF3 murine cells mutated for JAK2, CALR or MPL will be evaluated. (AU)