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IGFBP7 action on TGFb/p53 pathways and corticoids resistance in Acute Lymphoblastic Leukemia

Grant number: 19/04943-3
Support Opportunities:Scholarships in Brazil - Doctorate
Start date: June 01, 2019
End date: August 31, 2023
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:José Andrés Yunes
Grantee:Leonardo Luís Artico
Host Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
Associated scholarship(s):22/04464-0 - Insulin signaling in metabolic diseases: the role of IGFBP7 in adipose tissue metabolic function, BE.EP.DR

Abstract

Acute Lymphoblastic Leukemia (LLA) is the most common type of Cancer in childhood, accounting for about 30% of all Cancers and 80% of all leukemias occurring up to the age of 15 years. In the previous work, we verified that leukemic cells secrete several proteins, among them IGFBP7, which together with their ligands (insulin, IGF1 and IGF2) stimulate bone marrow stromal cells to produce asparagine, creating a contrary dynamic to the action of L-asparaginase (chemotherapy extensively used in ALL treatment). However, data recently submitted for publication show that IGFBP7 can act in an autocrine and stromal independent manner, contributing to the greater progression of ALL both in vitro and in vivo. In addition, preliminary results indicate that IGFBP7 protects ALL against cytostatic actions mediated by corticoid drugs, in order to antagonize the tumor suppressor activity of TGFb/p53 pathways, reducing nuclear translocation of the glucocorticoid receptor (GR). Based on preliminary results and the known relevance of the TGFb/p53 pathways for oncogenesis, we propose to characterize the interactions between the TGFb and the glucocorticoid receptor (GR) and their inhibition by IGFBP7 in ALL. More specifically, we intend to (1) confirm that IGFBP7 blocks the activation of the canonical pathway of TGFb/Smad and p53, mediated by TGFb1 and dexamethasone in ALL; (2) to characterize the physical interactions between GR/Smads and their modulation in response to stimuli with IGFBP7, TGFb1 and/or dexamethasone; (3) determining the physical ligands of IGFBP7 in ALL; and (4) to evaluate the therapeutic efficacy of anti-IGFBP7 antibody in mice transplanted with patient ALL xenograft and the synergistic effects mediated by dexamethasone. (AU)

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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)
MENEGHETTI, DALILA; CEZAROTTO, VERCIANE SCHNEIDER; DO NASCIMENTO, NATALIA PAIVA; MIGITA, NATACHA AZUSSA; CORREA, JULIANA RONCHI; RICCIO, MARIA FRANCESCA; ZAMBALDI, LILIAN GIROTTO; YUNES, JOSE ANDRES; ARTICO, LEONARDO LUIS. Hydroalcoholic leaves extract of Vaccinium ashei Reade promotes cell cycle arrest and apoptosis on T-cell acute lymphoblastic leukemia. NATURAL PRODUCT RESEARCH, . (19/04943-3)
CEMIN, FELIPE; ARTICO, LEONARDO LUIS; PIROLI, VANESSA; YUNES, JOSE ANDRES; FIGUEROA, CARLOS ALEJANDRO; ALVAREZ, FERNANDO. Superior in vitro biocompatibility in NbTaTiVZr(O) high-entropy metallic glass coatings for biomedical applications. Applied Surface Science, v. 596, p. 11-pg., . (19/18460-4, 19/04943-3, 18/24461-0)
ARTICO, LEONARDO LUIS; RUAS, JULIANA SILVEIRA; TEIXEIRA JUNIOR, JOSE RICARDO; MIGITA, NATACHA AZUSSA; SEGUCHI, GUSTAVO; SHI, XINGHUA; BRANDALISE, SILVIA REGINA; CASTILHO, ROGER FRIGERIO; YUNES, JOSE ANDRES. IGFBP7 Fuels the Glycolytic Metabolism in B-Cell Precursor Acute Lymphoblastic Leukemia by Sustaining Activation of the IGF1R-Akt-GLUT1 Axis. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 11, p. 14-pg., . (19/04943-3, 22/04464-0, 17/17728-8, 14/20015-5, 12/12802-1)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
ARTICO, Leonardo Luís. Insights mecanísticos sobre a ativação de IGF1R mediada por IGFBP7 e o metabolismo glicolítico na leucemia linfoide aguda. 2023. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.