Investigation of the antineoplastic potential of ezrin inhibition in acute Leukemia models

• Grant number: 20/12909-7
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2021
• End date: January 31, 2024
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: João Agostinho Machado Neto
• Grantee: Jean Carlos Lipreri da Silva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 22/04987-3 - Investigation of ezrin inhibitors on Rho GTPase-mediated migratory and invasive activity in acute lymphoblastic leukemia cells, BE.EP.DD

Abstract

Acute Leukemias are aggressive neoplasms characterized by clonal proliferation with replacement and accumulation of neoplastic cells (e20%) in bone marrow and other organs and can be classified as acute myeloid leukemia (AML) or Acute Lymphoblastic Leukemia (ALL) when there is involvement of myeloblasts or lymphoblasts, respectively. Despite great advances in understanding the complexity involved in the molecular changes of acute Leukemias, very little has been translated into new therapies. In preliminary analyzes using large-scale genomic data deposited by TCGA (The Cancer Genomics Atlas), the differential expression of EZR (which encodes the ezrin protein) was identified as a prognostic marker and initial analyzes suggest its therapeutic potential. Ezrin is a protein member of the ERM family and its function is to bind the actin cytoskeleton to the cell membrane and create a support for signaling molecules involved in important cellular processes. The identification of new molecular prognostic markers and signaling pathways/selective targets for pharmacological intervention is of interest in the study of acute Leukemias, which can improve clinical management and generate new opportunities for therapies. The objectives of this proposal are (I) to identify cytoskeleton regulatory genes, whose differential expression predicts the clinical outcome in patients with acute leukemia; (II) verify the impact of inhibition of selected genes on viability, proliferation, clonogenicity, apoptosis and modulation in signaling pathways in models of acute leukemia in vitro. (AU)

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)

LIPRERI DA SILVA, JEAN CARLOS; CARVALHO, MARIA FERNANDA LOPES; DE MIRANDA, LIVIA BASSANI LINS; DE ALMEIDA, BRUNA OLIVEIRA; LIMA, KELI; MACHADO-NETO, JOAO AGOSTINHO. NSC305787, a pharmacological ezrin inhibitor, exhibits antineoplastic activity in pancreatic cancer cells. INVESTIGATIONAL NEW DRUGS, v. N/A, p. 10-pg., 2022-04-28. (19/23864-7, 20/12909-7, 20/12748-3)