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 Opportunities: Regular Research Grants
• Start date: June 01, 2020
• End date: May 31, 2022
• 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 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

(24)

(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)

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)

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)

FERNANDES, JAQUELINE CRISTINA; FENERICH, BRUNA ALVES; ALVES-SILVA, ANTONIO BRUNO; FONSECA, NATASHA PEIXOTO; COELHO-SILVA, JUAN LUIZ; SCHEUCHER, PRISCILA SANTOS; REGO, EDUARDO MAGALHAES; FIGUEIREDO-PONTES, LORENA LOBO; MACHADO-NETO, JOAO AGOSTINHO; TRAINA, FABIOLA. Differential cytotoxic activity of pharmacological inhibitors of IGF1R-related pathways in JAK2(V617F) driven cells. TOXICOLOGY IN VITRO, v. 83, p. 7-pg., 2022-05-26. (13/08135-2, 17/19864-6, 15/02200-2, 16/14049-0, 19/23864-7)

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; 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)

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)

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)

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)

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)

DIAS FLORENCIO, KATHARINE GURGEL; EDSON, EVELLINE ARAUJO; DA SILVA FERNANDES, KEILLA SANTANA; MESQUITA LUIZ, JOAO PAULO; LIMA PINTO, FRANCISCO DAS CHAGAS; LOIOLA PESSOA, OTILIA DEUSDENIA; CUNHA, FERNANDO DE QUEIROZ; MACHADO-NETO, JOAO AGOSTINHO; WILKE, DIEGO VERAS. Chromomycin A(5) induces bona fide immunogenic cell death in melanoma. FRONTIERS IN IMMUNOLOGY, v. 13, p. 19-pg., 2022-11-09. (13/08216-2, 19/23864-7)

LINS DE MIRANDA, LIVIA BASSANI; LIMA, KELI; COELHO-SILVA, JUAN LUIZ; TRAINA, FABIOLA; KOBAYASHI, SUSUMU S.; MACHADO-NETO, JOAO AGOSTINHO. NT157 exerts antineoplastic activity by targeting JNK and AXL signaling in lung cancer cells. SCIENTIFIC REPORTS, v. 12, n. 1, p. 11-pg., 2022-10-12. (19/23864-7, 20/12748-3, 21/11606-3)

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; LIMA, KELI; COSTA-LOTUFO, LETICIA VERAS; MACHADO-NETO, JOAO AGOSTINHO. Cellular and Molecular Effects of Eribulin in Preclinical Models of Hematologic Neoplasms. CANCERS, v. 14, n. 24, p. 15-pg., 2022-12-01. (21/01460-1, 19/23864-7, 19/01700-2, 21/11606-3)

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)

SALATA, GIOVANNA C.; MALAGO, ISABELLA D.; LOPES, LUCIANA B.. A Lipid-Based In Situ-Forming Hexagonal Phase for Prolonged Retention and Drug Release in the Breast Tissue. AAPS PHARMSCITECH, v. 23, n. 7, p. 14-pg., 2022-09-19. (14/50928-2, 18/13877-1, 19/23864-7)

LIMA, KELI; VICARI, HUGO PASSOS; ELIAS GODOY CARLOS, JORGE ANTONIO; LIPRERI DA SILVA, JEAN CARLOS; DE FIGUEIREDO-PONTES, LORENA LOBO; REGO, EDUARDO MAGALHAES; MACHADO-NETO, JOAO AGOSTINHO. Obatoclax reduces cell viability of acute myeloid leukemia cell lines independently of their sensitivity to venetoclax. Hematology, Transfusion and Cell Therapy, v. 44, n. 1, p. 4-pg., 2022-02-26. (19/01700-2, 19/23864-7, 18/19372-9)

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)

LIMA, KELI; PEREIRA-MARTINS, DIEGO ANTONIO; LINS DE MIRANDA, LIVIA BASSANI; COELHO-SILVA, JUAN LUIZ; LEANDRO, GIOVANA DA SILVA; WEINHAUSER, ISABEL; CAVAGLIERI, RITA DE CASSIA; LEAL, ALINE DE MEDEIROS; DA SILVA, WELLINGTON FERNANDES; ALENCAR DE LIMA LANGE, ANA PAULA; et al. The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy. BLOOD CANCER JOURNAL, v. 12, n. 11, p. 11-pg., 2022-11-09. (15/09228-0, 20/12842-0, 19/23864-7, 21/11606-3, 17/23117-1)

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)

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; DE MIRANDA, LIVIA BASSANI LINS; GARNIQUE, ANALI DEL MILAGRO BERNABE; DE ALMEIDA, BRUNA OLIVEIRA; DO NASCIMENTO, MARIANE CRISTINA; ALCANTARA, GUILHERME AUGUSTO SOUSA; MACHADO-SANTELLI, GLAUCIA MARIA; REGO, EDUARDO MAGALHAES; MACHADO-NETO, JOAO AGOSTINHO. The Multikinase Inhibitor AD80 Induces Mitotic Catastrophe and Autophagy in Pancreatic Cancer Cells. CANCERS, v. 15, n. 15, p. 14-pg., 2023-08-01. (19/23864-7, 21/11606-3, 20/12842-0, 22/03316-8, 19/25421-5)