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Interactions between emerging therapeutic targets and developmental pathways associated with tumorigenesis: emphasis on pediatric malignancies

Grant number: 14/20341-0
Support type:Research Projects - Thematic Grants
Duration: September 01, 2016 - August 31, 2022
Field of knowledge:Health Sciences - Medicine - Maternal and Child Health
Principal researcher:Luiz Gonzaga Tone
Grantee:Luiz Gonzaga Tone
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Pesquisadores principais:
Carlos Alberto Scrideli ; Carlos Gilberto Carlotti Jr
Assoc. researchers: Ana Luiza Ongaro Seidinger Conte ; Edgard Eduard Engel ; Elvis Terci Valera ; Helio Rubens Machado ; Izilda Aparecida Cardinalli ; José Andrés Yunes ; Luciano Neder Serafini ; Paula Cristina dos Santos ; Ricardo Santos de Oliveira ; Silvia Regina Brandalise ; Simone dos Santos Aguiar ; Suely Kazue Nagahashi Marie ; Vitor Marcel Faça ; Wilson Araújo da Silva Junior
Associated scholarship(s):21/00932-7 - Evaluation of expression and prognostic value of CXCL9 and CXCL10 genes in pediatric adrenocortical tumors, BP.IC
20/16426-0 - Technical support in the validation of the hub gene PRICKLE1 by molecular biology analyzes and functional assays, and support in the laboratory routine., BP.TT
20/04850-2 - Technical support to assist in target validation, by analysis of molecular biology and silicon analysis, from results obtained for pediatric adrenocortical tumor (ACT); and support in the laboratory routine, BP.TT
+ associated scholarships 17/26160-5 - Musashi-1 gene in medulloblastoma group 3 and 4, BP.DR
19/19772-0 - Technical support in laboratory routine and target validation through functional assays and molecular biology analysis, BP.TT
18/23372-4 - Study of the effects of DNA demethylation on genes associated with developmental pathways in pediatric Ependymomas, BP.DR
19/00547-6 - Technical support in the laboratory routine and the search for new therapeutic targets using bioinformatics tools, BP.TT
18/04477-0 - Crosstalk signaling between TGF-beta and Wnt/beta-catenin pathways in Adrenocortical Tumors, BP.PD
18/05401-7 - "Investigation and validation of methylated hub genes in medulloblastoma", BP.PD
17/06511-8 - Investigation of Smad2/3-YAP complex as a chemoresistant factor in TP53, BP.PD
16/19820-6 - Investigation of new therapeutic targets from transcriptional networks of genes of the mitotic spindle associated with embryonic developmental pathways in the ependymoma: focus on molecular subgroups of worst outcome, BP.DR
16/19799-7 - Research therapeutic targets from gene expression networks of members of the TGF-b pathway associated with tumor progression of ependymomas of worse prognosis, BP.DR
16/23972-6 - Molecular classification of pediatric ependymomas, BP.MS
16/24117-2 - Notch signaling and the role of Notch/Skp2 axis in the tumorigenesis of Medulloblastoma, BP.PD - associated scholarships

Abstract

Currently, even with intensive multimodal treatment, 20% of children and adolescents with cancer will still die due to disease and over 40% of survivors develop sequelae that affect the adult quality of life. Therefore, more effective and safer treatment options for children with cancer are still needed to increase cure rates, decrease toxicity and to minimize the risk of long term effects on survivors. The biology of pediatric cancers are intrinsically associated with dysregulation of signaling pathways that control normal embryonic development. Among these pathways are Wnt, Shh and Notch, and TGF-², which also play an important role in carcinogenesis and are involved in tumor chemo-and radio-resistance. The study of these pathways in the context of the biology of pediatric tumors may constitute a new field for the identification of target genes and understanding of the long-term effects caused by the different treatment modalities of infant tumors. Thus, this project aims to identify co-expression networks associated with the transcriptional modules of the above mentioned pathways in different pediatric tumors (medulloblastoma, ependymoma, Ewing's sarcoma and adrenal carcinoma). From these data, genes considered plausible therapeutic targets (those previously studied by our group, those with therapeutic/prognostic value established in the literature or genes that have a promising scientific value for each studied tumor) will be validated and subsequently investigated in in vitro and in vivo models through different techniques. This research may provide new molecular perspectives, both to elucidate the specific mechanisms involved in pediatric tumor biology, as for the identification of new therapeutic strategies for treating this cohort. (AU)

Articles published in Agência FAPESP Newsletter about the research grant:
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Scientific publications (13)
(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)
VERONEZ, LUCIANA C.; DAS CHAGAS, PABLO F.; CORREA, CAROLINA A. P.; BARONI, MIRELLA; DA SILVA, KETERYNE R.; NAGANO, LUIS F.; BORGES, KLEITON S.; QUEIROZ, ROSANE G. P.; TONE, LUIZ G.; SCRIDELI, CARLOS A. MSI2 expression in adrenocortical carcinoma: Association with unfavorable prognosis and correlation with steroid and immune-related pathways. Journal of Cellular Biochemistry, SEP 2021. Web of Science Citations: 0.
DE SOUSA, GRAZIELLA RIBEIRO; LIRA, REGIA CAROLINE PEIXOTO; DE ALMEIDA MAGALHAES, TACIANI; DA SILVA, KETERYNE RODRIGUES; NAGANO, LUIS FERNANDO PEINADO; SAGGIORO, FABIANO PINTO; BARONI, MIRELLA; MARIE, SUELY KAZUE NAGAHASHI; OBA-SHINJO, SUELI MIEKO; BRANDELISE, SILVIA; DE PAULA QUEIROZ, ROSANE GOMES; BRASSESCO, MARIA SOL; SCRIDELI, CARLOS ALBERTO; TONE, LUIZ GONZAGA; VALERA, ELVIS TERCI. A coordinated approach for the assessment of molecular subgroups in pediatric ependymomas using low-cost methods. JOURNAL OF MOLECULAR MEDICINE-JMM, v. 99, n. 8, p. 1101-1113, AUG 2021. Web of Science Citations: 1.
MARIA, ANDREA GUTIERREZ; BORGES, KLEITON SILVA; LIRA, R. C. P.; THOME, CAROLINA HASSIB; BERTHON, ANNABEL; DROUGAT, LUDIVINE; KISELJAK-VASSILIADES, KATJA; WIERMAN, MARGARET E.; FAUCZ, FABIO R.; FACA, VITOR MARCEL; TONE, LUIZ GONZAGA; STRATAKIS, CONSTANTINE A. Inhibition of Aurora kinase A activity enhances the antitumor response of beta-catenin blockade in human adrenocortical cancer cells. Molecular and Cellular Endocrinology, v. 528, MAY 15 2021. Web of Science Citations: 0.
DE SOUSA, GRAZIELLA RIBEIRO; LIRA, REGIA CAROLINE PEIXOTO; DE ALMEIDA MAGALHAES, TACIANI; DA SILVA, KETERYNE RODRIGUES; NAGANO, LUIS FERNANDO PEINADO; SAGGIORO, FABIANO PINTO; BARONI, MIRELLA; MARIE, SUELY KAZUE NAGAHASHI; OBA-SHINJO, SUELI MIEKO; BRANDELISE, SILVIA; DE PAULA QUEIROZ, ROSANE GOMES; BRASSESCO, MARIA SOL; SCRIDELI, CARLOS ALBERTO; TONE, LUIZ GONZAGA; VALERA, ELVIS TERCI. A coordinated approach for the assessment of molecular subgroups in pediatric ependymomas using low-cost methods. JOURNAL OF MOLECULAR MEDICINE-JMM, v. 99, n. 8 APR 2021. Web of Science Citations: 0.
DA SILVA FEITOSA, JOSE ANTONIO; DAS CHAGAS, PABLO FERREIRA; DE SOUSA, GRAZIELLA RIBEIRO; DE PAULA QUEIROZ, ROSANE GOMES; VEIGA CRUZEIRO, GUSTAVO ALENCASTRO; TONE, LUIZ GONZAGA; BORGES, KLEITON SILVA; VALERA, ELVIS TERCI. Frequency of theTP53p.R337H mutation in a Brazilian cohort of pediatric patients with solid tumors. MOLECULAR BIOLOGY REPORTS, v. 47, n. 8 JUL 2020. Web of Science Citations: 0.
DE ALMEIDA MAGALHAES, TACIANI; CRUZEIRO, GUSTAVO ALENCASTRO VEIGA; DE SOUSA, GRAZIELLA RIBEIRO; DA SILVA, KETERYNE RODRIGUES; LIRA, REGIA CAROLINE PEIXOTO; SCRIDELI, CARLOS ALBERTO; TONE, LUIZ GONZAGA; VALERA, ELVIS TERCI; BORGES, KLEITON SILVA. Notch pathway in ependymoma RELA-fused subgroup: upregulation and association with cancer stem cells markers expression. Cancer Gene Therapy, v. 27, n. 6, p. 509-512, JUN 2020. Web of Science Citations: 0.
DOS SANTOS KLINGER, PAULO HENRIQUE; ALBERICI DELSIN, LARA ELIS; VEIGA CRUZEIRO, GUSTAVO ALENCASTRO; ANDRADE, AUGUSTO FARIA; PEIXOTO LIRA, REGIA CAROLINE; DE ANDRADE, PAMELA VIANI; DAS CHAGAS, PABLO FERREIRA; DE PAULA QUEIROZ, ROSANE GOMES; TREVISAN, FELIPE AMSTALDEN; DE OLIVEIRA, RICARDO SANTOS; SCRIDELI, CARLOS ALBERTO; TONE, LUIZ GONZAGA; VALERA, ELVIS TERCI. Arsenic Trioxide exerts cytotoxic and radiosensitizing effects in pediatric Medulloblastoma cell lines of SHH Subgroup. SCIENTIFIC REPORTS, v. 10, n. 1 APR 22 2020. Web of Science Citations: 0.
MAGALHAES, TACIANI DE ALMEIDA; BORGES, KLEITON SILVA; DE SOUSA, GRAZIELLA RIBEIRO; BRANDALISE, SILVIA REGINA; SEIDINGER, ANA LUIZA; SCRIDELI, CARLOS ALBERTO; OBA-SHINJO, SUELI MIEKO; YUNES, JOSE ANDRES; TONE, LUIZ GONZAGA. The TP53 p.R337H mutation is uncommon in a Brazilian cohort of pediatric patients diagnosed with ependymoma. NEUROLOGICAL SCIENCES, v. 41, n. 3, p. 691-694, MAR 2020. Web of Science Citations: 0.
DAS CHAGAS, PABLO FERREIRA; BARONI, MIRELLA; BRASSESCO, MARIA SOL; TONE, LUIZ GONZAGA. Interplay between the RNA binding-protein Musashi and developmental signaling pathways. JOURNAL OF GENE MEDICINE, v. 22, n. 1 JAN 2020. Web of Science Citations: 0.
DE SOUSA, GRAZIELLA RIBEIRO; NAGAHASHI MARIE, SUELY KAZUE; OBA-SHINJO, SUELI MIEKO; ZAMBELLI RAMALHO, LEANDRA NAIRA; TONE, LUIZ GONZAGA; VALERA, ELVIS TERCI. A novel type of C11orf95-LOC-RELA fusion in a grade II supratentorial ependymoma: report of a case with literature review. CHILD'S NERVOUS SYSTEM, v. 35, n. 4, p. 689-694, APR 2019. Web of Science Citations: 0.
VEIGA CRUZEIRO, GUSTAVO ALENCASTRO; SALOMAO, KARINA BEZERRA; OLIVEIRA DE BIAGI, JR., CARLOS ALBERTO; BAUMGARTNER, MARTIN; STURM, DOMINIK; PEIXOTO LIRA, REGIA CAROLINE; MAGALHAES, TACIANI DE ALMEIDA; MILAN, MIRELLA BARONI; SILVEIRA, VANESSA DA SILVA; SAGGIORO, FABIANO PINTO; DE OLIVEIRA, RICARDO SANTOS; DOS SANTOS KLINGER, PAULO HENRIQUE; SEIDINGER, ANA LUIZA; YUNES, JOSE ANDRES; DE PAULA QUEIROZ, ROSANE GOMES; OBA-SHINJO, SUELI MIEKO; SCRIDELI, CARLOS ALBERTO; KAZUE NAGAHASHI, SUELY MARIE; TONE, LUIZ GONZAGA; VALERA, ELVIS TERCI. A simplified approach using Taqman low-density array for medulloblastoma subgrouping. ACTA NEUROPATHOLOGICA COMMUNICATIONS, v. 7, MAR 4 2019. Web of Science Citations: 0.
GERON, LENISA; SALOMAO, KARINA BEZERRA; BORGES, KLEITON SILVA; ANDRADE, AUGUSTO FARIA; PEREIRA CORREA, CAROLINA ALVES; SCRIDELI, CARLOS ALBERTO; TONE, LUIZ GONZAGA. Molecular characterization of Wnt pathway and function of -catenin overexpression in medulloblastoma cell lines. Cytotechnology, v. 70, n. 6, p. 1713-1722, DEC 2018. Web of Science Citations: 0.
SALOMAO, KARINA BEZERRA; VEIGA CRUZEIRO, GUSTAVO ALENCASTRO; BONFIM-SILVA, RICARDO; GERON, LENISA; RAMALHO, FERNANDO; SAGGIORO, FABIANO PINTO; SERAFINI, LUCIANO NEDER; ANTUNES MORENO, DANIEL; DE PAULA QUEIROZ, ROSANE GOMES; AGUIAR, SIMONE DOS SANTOS; CARDINALLI, IZILDA; YUNES, JOSE ANDRES; BRANDALISE, SILVIA REGINA; BRASSESCO, MARIA SOL; SCRIDELI, CARLOS ALBERTO; TONE, LUIZ GONZAGA. Reduced hydroxymethylation characterizes medulloblastoma while TET and IDH genes are differentially expressed within molecular subgroups. JOURNAL OF NEURO-ONCOLOGY, v. 139, n. 1, p. 33-42, AUG 2018. Web of Science Citations: 0.

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