Comprehensive analysis of genomic data for identification and validation of novel therapeutic targets involved in cellular cytoskeleton regulation in acute leukemia

• Grant number: 19/23864-7
• Support type: Regular Research Grants
• Duration: June 01, 2020 - May 31, 2022
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal researcher: João Agostinho Machado Neto
• Grantee: João Agostinho Machado Neto
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Acute leukemias are aggressive hematological malignancies characterized by clonal proliferation with replacement and accumulation of neoplastic cells in the bone marrow, peripheral blood and other organs that suppress normal hematopoiesis. Despite the great advances in understanding the complexity involved in the molecular changes of acute leukemia in recent years, very little has been translated into novel therapies. Major investments have been made in the generation of large-scale genomic data, including public deposition of mutational profile and gene expression data in patients with hematological malignancies, a unique tool for generating and testing hypotheses based on differential expression or prognostic impact of genes. Cell cytoskeleton is an attractive therapeutic target, as this structure regulates vital cell functions and has been used as target for decades in oncology. However, the low selectivity to cancer cells of this class of drugs results in serious adverse effects. Our research group has sought to identify genes/proteins related to the regulation of actin fibers, microtubules and intermediate filaments selectively expressed or activated in leukemia cells to serve as targets for pharmacological intervention. The objectives of this project are (i) To identify cellular cytoskeleton regulatory genes, whose differential expression predicts clinical outcome in patients with acute leukemia; (ii) Verify the impact of inhibition (pharmacological and/or genetic) of the selected genes on viability, proliferation, clonogenicity, apoptosis and modulation in signaling pathways in in vitro and in vivo acute leukemia models. Our expectation is to generate proof-of-concept for the identification of new targets and the development of cell cytoskeletal selective treatments for cancer cells. (AU)

Scientific publications

(11)

(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)

DE ALMEIDA, LARISSA COSTA; CALIL, FELIPE ANTUNES; MACHADO-NETO, JOAO AGOSTINHO; COSTA-LOTUFO, LETICIA VERAS. DNA damaging agents and DNA repair: From carcinogenesis to cancer therapy. CANCER GENETICS, v. 252, p. 6-24, APR 2021. (19/23864-7)

VICARI, HUGO PASSOS; LIMA, KELI; GOMES, RALPH DA COSTA; FERNANDES, DANIARA CRISTINA; LIPRERI DA SILVA, JEAN CARLOS; RODRIGUES JUNIOR, MANOEL TRINDADE; BARROSO DE OLIVEIRA, ALINE SILVA; DOS SANTOS, RICARDO NASCIMENTO; ANDRICOPULO, ADRIANO DEFINI; COELHO, FERNANDO; et al. Synthetic cyclopenta [b] indoles exhibit antineoplastic activity by targeting microtubule dynamics in acute myeloid leukemia cells. European Journal of Pharmacology, v. 894, MAR 5 2021. (19/01700-2, 13/07600-3, 19/23864-7, 15/17177-6, 17/24993-0)

LIPRERI DA SILVA, JEAN CARLOS; COELHO-SILVA, JUAN LUIZ; LIMA, KELI; VICARI, HUGO PASSOS; LAZARINI, MARIANA; COSTA-LOTUFO, LETICIA VERAS; TRAINA, FABIOLA; MACHADO-NETO, JOAO AGOSTINHO. Comprehensive analysis of cytoskeleton regulatory genes identifies ezrin as a prognostic marker and molecular target in acute myeloid leukemia. CELLULAR ONCOLOGY, v. 44, n. 5, p. 1105-1117, OCT 2021. (17/24993-0, 19/23864-7, 15/17177-6)

HIRAKATA, CAMILA; LIMA, KELI; DE ALMEIDA, BRUNA OLIVEIRA; DE MIRANDA, LIVIA BASSANI LINS; FLORENCIO, KATHARINE GURGEL DIAS; FURTADO, LUCIANA COSTA; COSTA-LOTUFO, LETICIA VERAS; MACHADO-NETO, JOAO AGOSTINHO. Targeting glioma cells by antineoplastic activity of reversine. Oncology Letters, v. 22, n. 2, AUG 2021. (15/17177-6, 18/19372-9, 19/23864-7)

PARADA, CAROLINA A.; DE OLIVEIRA, IVAN PIRES; GEWEHR, MAYARA C. F.; MACHADO-NETO, JOAO AGOSTINHO; LIMA, KELI; EICHLER, ROSANGELA A. S.; LOPES, LUCIA R.; BECHARA, LUIZ R. G.; FERREIRA, JULIO C. B.; FESTUCCIA, WILLIAM T.; et al. ffect of FKBP12-Derived Intracellular Peptides on Rapamycin-Induced FKBP-FRB Interaction and Autophag. ELL, v. 11, n. 3, FEB 2022. (19/25049-9, 13/07937-8, 19/27149-0, 17/02201-4, 16/04000-3, 19/07332-5, 19/23864-7)

DE ALMEIDA, BRUNA OLIVEIRA; MACHADO-NETO, JOAO AGOSTINHO. Emerging functions for ANKHD1 in cancer-related signaling pathways and cellular processes. BMB REPORTS, v. 53, n. 8, p. 413-418, AUG 31 2020. (19/25421-5, 19/23864-7, 17/24993-0)

CARLOS, JORGE ANTONIO ELIAS GODOY; LIMA, KELI; COSTA-LOTUFO, LETICIA VERAS; LEITAO, ANDREI; MACHADO-NETO, JOAO AGOSTINHO. AD80, a multikinase inhibitor, exhibits antineoplastic effects in acute leukemia cellular models targeting the PI3K/STMN1 axis. INVESTIGATIONAL NEW DRUGS, v. 39, n. 4, p. 1139-1149, AUG 2021. (17/24993-0, 15/17177-6, 18/15904-6, 18/19372-9, 19/23864-7)

SALATA, GIOVANNA CASSONE; MALAGO, ISABELLA D.; CARVALHO DARTORA, VANESSA F. M.; MARCAL PESSOA, ANA FLAVIA; DE ABREU FANTINI, MARCIA CARVALHO; COSTA, SORAIA K. P.; MACHADO-NETO, JOAO AGOSTINHO; LOPES, LUCIANA B.. Microemulsion for Prolonged Release of Fenretinide in the Mammary Tissue and Prevention of Breast Cancer Development. MOLECULAR PHARMACEUTICS, v. 18, n. 9, p. 3401-3417, SEP 6 2021. (14/50928-2, 19/23864-7, 16/06146-5, 17/23213-0, 18/13877-1)

MATEUS REIS-SILVA, CATARINA SOFIA; BRANCO, PAOLA CRISTINA; LIMA, KELI; SILVA, FABIANA LIMA; HRIHOROWITSCH MORENO, PAULO ROBERTO; GUALLAR, VICTOR; COSTA-LOTUFO, LETICIA VERAS; MACHADO-NETO, JOAO AGOSTINHO. Embelin potentiates venetoclax-induced apoptosis in acute myeloid leukemia cells. TOXICOLOGY IN VITRO, v. 76, OCT 2021. (17/09022-8, 19/23864-7, 15/17177-6, 18/06522-2)

VICARI, HUGO PASSOS; COELHO-SILVA, JUAN LUIZ; PEREIRA-MARTINS, DIEGO A.; LUCENA-ARAUJO, ANTONIO ROBERTO; LIMA, KELI; LIPRERI DA SILVA, JEAN CARLOS; SCHEUCHER, PRISCILA SANTOS; KOURY, LUISA C.; DE MELO, RAUL A.; BITTENCOURT, ROSANE; et al. STMN1 is highly expressed and contributes to clonogenicity in acute promyelocytic leukemia cells. INVESTIGATIONAL NEW DRUGS, NOV 2021. (19/01700-2, 20/12842-0, 17/23117-1, 19/23864-7, 17/24993-0)

LIMA, KELI; LOPES, LUCIA ROSSETTI; MACHADO-NETO, JOAO AGOSTINHO. Exploring redox vulnerabilities in JAK2(V617F)-positive cellular models. Hematology, Transfusion and Cell Therapy, v. 43, n. 4, p. 430-436, OCT-DEC 2021. (19/23864-7, 13/07937-8)