Investigation of Stathmin 1 and microtubule instability in phenotype of hematological neoplasms

• Grant number: 17/24993-0
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2018
• End date: April 30, 2020
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: João Agostinho Machado Neto
• Grantee: João Agostinho Machado Neto
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Acute leukemias comprise a group of hematological malignancies characterized by the expansion of blasts in bone marrow and peripheral blood, which is mainly due to the loss of differentiation ability of stem cells to functional cells in terminal stage, deregulation of proliferation and resistance to apoptosis. The mortality of adult patients with acute leukemia is very high, making it imperative to identify new molecular markers and signaling pathways that may be useful in prognostic definition, therapeutic response and the development of new treatment options. Stathmin 1 is a microtubule destabilizing protein that includes multiple signaling pathways and has been described as potentially regulated by oncogenes associated with hematological malignancies, including JAK2V617F, PML-RAR± and BCR-ABL1. In addition, Stathmin 1 is highly expressed in leukemia cells and Stathmin 1 inhibition reduces the proliferation and clonogenicity. However, the clinical impact of Stathmin 1 expression, as well as, the consolidation of this protein as a potential therapeutic target in hematological malignancies remains poor explored. The aims of the present project are (i) to investigate the impact of Stathmin 1 expression in the clinical outcome of a well-characterized cohort of patients with acute promyelocytic leukemia, (ii) to investigate the effects of Stathmin 1 inhibition in leucemia cells in vitro and in vivo models, (iii) to identify and/or validate compounds capable of inhibiting Stathmin 1 and/or cause microtubules stability and to characterize them at cellular and molecular level. (AU)

Scientific publications

(14)

(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; 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, JUL 2021. (17/24993-0, 15/17177-6, 19/23864-7)

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)

LIMA, KELI; COELHO-SILVA, JUAN LUIZ; KINKER, GABRIELA SARTI; PEREIRA-MARTINS, DIEGO ANTONIO; TRAINA, FABIOLA; CARLOS MAGNO FERNANDES, PEDRO AUGUSTO; MARKUS, REGINA PEKELMANN; LUCENA-ARAUJO, ANTONIO ROBERTO; MACHADO-NETO, JOAO AGOSTINHO. PIP4K2A and PIP4K2C transcript levels are associated with cytogenetic risk and survival outcomes in acute myeloid leukemia. CANCER GENETICS, v. 233, p. 56-66, APR 2019. (17/24993-0)

DE ALMEIDA, LARISSA COSTA; BAUERMEISTER, ANELIZE; REZENDE-TEIXEIRA, PAULA; DOS SANTOS, EVELYNE ALVES; BERALDO DE MORAES, LUIZ ALBERTO; MACHADO-NETO, JOAO AGOSTINHO; COSTA-LOTUFO, LETICIA VERAS. Pradimicin-IRD exhibits antineoplastic effects by inducing DNA damage in colon cancer cells. Biochemical Pharmacology, v. 168, p. 38-47, OCT 2019. (17/17648-4, 15/17177-6, 18/17595-0, 17/24993-0, 14/50926-0)

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. (17/24993-0, 19/23864-7, 19/25421-5)

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)

DE ALMEIDA, LARISSA COSTA; CALIL, FELIPE ANTUNES; MORENO, NATALIA CESTARI; REZENDE-TEIXEIRA, PAULA; DE MORAES, LUIZ ALBERTO BERALDO; JIMENEZ, PAULA CHRISTINE; MENCK, CARLOS FREDERICO MARTINS; MACHADO-NETO, JOAO AGOSTINHO; COSTA-LOTUFO, LETICIA VERAS. Exploring pradimicin-IRD antineoplastic mechanisms and related DNA repair pathways. Chemico-Biological Interactions, v. 371, p. 10-pg., 2023-01-14. (17/24993-0, 18/17595-0, 14/50926-0, 19/23864-7, 21/11606-3, 19/19435-3, 15/17177-6)

LIMA, KELI; ELIAS GODOY CARLOS, JORGE ANTONIO; ALVES-PAIVA, RAQUEL DE MELO; VICARI, HUGO PASSOS; DE SOUZA SANTOS, FABIO PIRES; HAMERSCHLAK, NELSON; COSTA-LOTUFO, LETICIA VERAS; TRAINA, FABIOLA; MACHADO-NETO, JOAO AGOSTINHO. Reversine exhibits antineoplastic activity in JAK2(V)(617)(F)-positive myeloproliferative neoplasms. SCIENTIFIC REPORTS, v. 9, JUL 9 2019. (17/24993-0)

DE ALMEIDA, BRUNA O.; DE ALMEIDA, LARISSA C.; COSTA-LOTUFO, LETICIA, V; MACHADO-NETO, JOAO A.. ANKHD1 contributes to the malignant phenotype of triple-negative breast cancer cells. Cell Biology International, v. 46, n. 9, p. 14-pg., 2022-07-16. (17/17648-4, 19/23864-7, 15/17177-6, 17/24993-0)

DE ALMEIDA, LARISSA COSTA; CARLOS, JORGE ANTONIO ELIAS GODOY; REZENDE-TEIXEIRA, PAULA; MACHADO-NETO, JOAO AGOSRINHO; COSTA-LOTUFO, LETICIA VERAS. AD80, a multikinase inhibitor, as a potential drug candidate for colorectal cancer therapy. Life Sciences, v. 308, p. 9-pg., 2022-09-02. (18/19372-9, 17/24993-0, 18/17595-0, 19/23864-7, 21/11606-3, 15/17177-6)

ELIAS GODOY CARLOS, JORGE ANTONIO; LIMA, KELI; COELHO-SILVA, JUAN LUIZ; ALVES-PAIVA, RAQUEL DE MELO; MORENO, NATALIA CESTARI; VICARI, HUGO PASSOS; DE SOUZA SANTOS, FABIO PIRES; HAMERSCHLAK, NELSON; COSTA-LOTUFO, LETICIA VERAS; TRAINA, FABIOLA; et al. Reversine exerts cytotoxic effects through multiple cell death mechanisms in acute lymphoblastic leukemia. CELLULAR ONCOLOGY, v. 43, n. 6, AUG 2020. (17/24993-0, 15/17177-6, 18/19372-9)

PASSAIA, BARBARA DOS SANTOS; LIMA, KELI; KREMER, JEAN LUCAS; DA CONCEICAO, BARBARA BRITO; DE PAULA MARIANI, BEATRIZ MARINHO; LIPRERI DA SILVA, JEAN CARLOS; NOGUEIRA ZERBINI, MARIA CLAUDIA; BARISSON VILLARES FRAGOSO, MARIA CANDIDA; MACHADO-NETO, JOAO AGOSTINHO; PACICCO LOTFI, CLAUDIMARA FERINI. Stathmin 1 is highly expressed and associated with survival outcome in malignant adrenocortical tumours. INVESTIGATIONAL NEW DRUGS, v. 38, n. 3, p. 899-908, JUN 2020. (16/17285-6, 17/24993-0, 16/12381-7)

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)