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Effects of erlotinib and gefitinib therapy in combination with all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: in vitro, ex vivo and murine experimental model studies.

Grant number: 16/02713-2
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): July 01, 2016
Effective date (End): April 21, 2019
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Eduardo Magalhães Rego
Grantee:Luciana Yamamoto de Almeida
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The epidermal growth factor receptor (EGFR) is an important regulator of cell proliferation and differentiation. Changes in EGFR expression are associated with tumor growth and metastasis in solid tumors. On the other hand, there is scarce information in the literature about the participation of the EGFR pathway in hematological malignancies, including acute myeloid leukemia (AML). A previous study conducted in our laboratory showed that EGF (epidermal growth factor), EGFR ligand, showed prognostic value in patients with acute promyelocytic leukemia (APL), M3 subtype of AML, treated according to the International Consortium on LPA protocol. Interestingly, patients with non-small cell lung cancer (NSCLC) and synchronous AML treated with erlotinib, EGFR inhibitor used in the treatment of NSCLC, had regression of both neoplasias. However, it is important to note that the myeloblasts these patients did not express EGFR. Accordingly, another study showed that gefitinib, also inhibitor of EGFR, acted synergistically when combined with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) in myeloid differentiation of LPA cell lines negative for EGFR. Until now, the mechanism by which erlotinib and gefitinib interact with hematopoietic progenitors are not well known. Moreover, it is necessary to determine if these drugs induce cell differentiation of APL-derived cells in vivo. Therefore, in this study, we intend to evaluate the effects of erlotinib and gefitinib isolated or in combination with ATRA and ATO in APL cell lines, primary blasts and murine experimental model as well as elucidate the molecular targets of these drugs.

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Scientific publications (18)
(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)
TAKAHAMA JR, ADEMAR; DE LIMA, HELITON GUSTAVO; ITO, FABIO AUGUSTO; RIBEIRO-SILVA, ALFREDO; LEON, JORGE ESQUICHE. Epstein-Barr Virus-Positive Mucocutaneous Ulcer Mimicking Peri-Implantitis in a Patient With Systemic Lupus Erythematosus. JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY, v. 77, n. 5, p. 977-984, . (16/11419-0, 16/02713-2)
LUCIANA YAMAMOTO ALMEIDA; HEITOR ALBERGONI SILVEIRA; EVÂNIO VILELA SILVA; CAMILA DE OLIVEIRA BARBEIRO; JOAQUIM AUGUSTO DE PAULA; ANDREIA BUFALINO; ALFREDO RIBEIRO-SILVA; JORGE ESQUICHE LEÓN. EBV-negative lymphoepithelial-like carcinoma of the lower lip. Autopsy and Case Reports, v. 10, n. 1, . (16/11419-0, 18/12734-2, 16/02713-2)
LANGE, A. P.; ALMEIDA, L. Y.; ARAUJO SILVA, C. L.; SCHEUCHER, P. S.; CHAHUD, F.; KRAUSE, A.; BOHLANDER, S. K.; REGO, E. M.. CCAAT/enhancer-binding protein alpha (CEBPA) gene haploinsufficiency does not alter hematopoiesis or induce leukemia in Lck-CALM/AF10 transgenic mice. Brazilian Journal of Medical and Biological Research, v. 52, n. 6, . (16/02713-2, 13/08135-2, 11/17111-4)
SILVEIRA, HEITOR ALBERGONI; TORAL-RIZO, VICTOR HUGO; LARA-CARRILLO, EDITH; DOMINGUETE, MATHEUS HENRIQUE LOPES; SILVA, EVANIO VILELA; RIBEIRO-SILVA, ALFREDO; BUFALINO, ANDREIA; ALMEIDA, LUCIANA YAMAMOTO; LEON, JORGE ESQUICHE. Spongiotic hyperplasia of the oral mucosa: case series and immunohistochemical analysis. ORAL AND MAXILLOFACIAL SURGERY-HEIDELBERG, . (17/01438-0, 16/11419-0, 16/02713-2, 18/12734-2)
POLANCO, X. B. J.; BERTASSO, A. S.; SILVEIRA, H. A.; YAMAMOTO DE ALMEIDA, L.; ALMEIDA, L. K. Y.; DA SILVA, R. A. B.; DA SILVA, L. A. B.; DE ROSSI, A.; NELSON-FILHO, P.; LEON, J. E.. IgG4-positive plasma cells are more often detected in chronic periapical lesions arising from permanent rather than primary teeth. International Endodontic Journal, v. 54, n. 5, . (16/02713-2, 16/11419-0)
DE ALMEIDA, LUCIANA YAMAMOTO; PEREIRA-MARTINS, DIEGO ANTONIO; GOUVEA LIMA, ANA SILVIA; BAGGIO, MARCIA SUELI; DE ARAUJO KOURY, LUISA CORREA; LANGE, ANA PAULA; BASSI, SARAH CRISTINA; SCHEUCHER, PRISCILA SANTOS; REGO, EDUARDO MAGALHAES. Interleukin-8 is not a predictive biomarker for the development of the acute promyelocytic leukemia differentiation syndrome. BMC CANCER, v. 20, n. 1, . (13/08135-2, 16/02713-2, 17/23117-1)
DE ALMEIDA, LUCIANA YAMAMOTO; PEREIRA-MARTINS, DIEGO A.; WEINHAEUSER, ISABEL; ORTIZ, CESAR; CANDIDO, LARISSA A.; LANGE, ANA PAULA; DE ABREU, NAYARA F.; MENDONZA, SILVIA E. S.; DE DEUS WAGATSUMA, VIRGINIA M.; DO NASCIMENTO, MARIANE C.; et al. The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells. FRONTIERS IN ONCOLOGY, v. 11, . (17/00775-3, 16/17521-1, 10/16966-3, 15/09228-0, 17/23117-1, 13/08135-2, 13/11817-8, 11/18313-0, 11/17111-4, 16/02713-2, 17/08430-5)
NEVES-SILVA, RODRIGO; ALMEIDA, LUCIANA Y.; SILVEIRA, HEITOR A.; COLTURATO, CARLA B. N.; DUARTE, ANDRESSA; FERRISSE, TULIO M.; SILVA, EVANIO, V; VANZOLIN, BARBARA F.; BUFALINO, ANDREIA; RIBEIRO-SILVA, ALFREDO; et al. SMARCB1 (INI-1) and NUT immunoexpression in a large series of head and neck carcinomas in a Brazilian reference center. HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK, v. 42, n. 3, p. 11-pg., . (16/02713-2, 16/11419-0, 18/12734-2)
SILVA, EVANIO VILELA; ALMEIDA, LUCIANA YAMAMOTO; BORTOLETTO, KAREN CRISTINE; QUERO, ISABELA BARBOSA; JACOMINI, FERNANDA CAROLINA; BENEVENUTO DE ANDRADE, BRUNO AUGUSTO; SILVEIRA, HEITOR ALBERGONI; DUARTE, ANDRESSA; PETEAN, FLAVIO CALIL; ROCHA, EDUARDO MELANI; et al. Focal lymphocytic sialadenitis and ectopic germinal centers in oral reactive lesions and primary Sjogren's syndrome: a comparative study. RHEUMATOLOGY INTERNATIONAL, . (16/02713-2, 16/14636-2, 18/12734-2, 16/11419-0)
SILVA, EVANIO V.; SILVEIRA, HEITOR A.; MESQUITA, ANA T. M.; ALMEIDA, LUCIANA Y.; RIBEIRO-SILVA, ALFREDO; LEON, JORGE E.. Elastofibromatous lesion as a differential diagnosis of white lesions of the oral mucosa. JOURNAL OF CUTANEOUS PATHOLOGY, v. 47, n. 3, p. 307+, . (18/12734-2, 16/11419-0, 16/02713-2)
NEVES-SILVA, RODRIGO; ALMEIDA, LUCIANA Y.; SILVEIRA, HEITOR A.; COLTURATO, CARLA B. N.; DUARTE, ANDRESSA; FERRISSE, TULIO M.; SILVA, V, EVANIO; VANZOLIN, BARBARA F.; BUFALINO, ANDREIA; RIBEIRO-SILVA, ALFREDO; et al. SMARCB1 (INI-1) and NUT immunoexpression in a large series of head and neck carcinomas in a Brazilian reference center. HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK, . (18/12734-2, 16/11419-0, 16/02713-2)
DE ALMEIDA, LUCIANA YAMAMOTO; REGO, EDUARDO MAGALHAES. Is the EGFR pathway relevant for the pathogenesis but not for treatment of acute myeloid leukemia?. JOURNAL OF CANCER METASTASIS AND TREATMENT, v. 7, p. 10-pg., . (16/02713-2, 13/08135-2)
DA MOTTA, RAPHAEL J. G.; ALMEIDA, LUCIANA YAMAMOTO; VILLAFUERTE, KELLY R. V.; RIBEIRO-SILVA, ALFREDO; LEON, JORGE E.; TIRAPELLI, CAMILA. FOXP3+and CD25+cells are reduced in patients with stage IV, grade C periodontitis: A comparative clinical study. JOURNAL OF PERIODONTAL RESEARCH, v. 55, n. 3, . (16/11419-0, 13/08589-3, 16/02713-2)
FERRISSE, TULIO M.; ALMEIDA, LUCIANA Y.; SILVEIRA, HEITOR A.; DE OLIVEIRA, ANALU B.; BUFALINO, ANDREIA; LEON, JORGE E.. Benign atypical intralymphatic CD30+lymphoid proliferation with activated regulatory T-cell phenotype in the oral cavity. JOURNAL OF CUTANEOUS PATHOLOGY, v. 46, n. 11, . (18/12734-2, 16/11419-0, 16/02713-2)
SILVEIRA, HEITOR ALBERGONI; ALMEIDA, LUCIANA YAMAMOTO; WEEGE NONAKA, CASSIANO FRANCISCO; ALVES, POLLIANNA MUNIZ; RIBEIRO-SILVA, ALFREDO; LEON, JORGE ESQUICHE. Myoepithelial carcinoma with rhabdoid features in the maxillary sinus: Immunohistochemical and in situ hybridization analysis of a rare case. Oral Oncology, v. 93, p. 116-119, . (16/02713-2, 18/12734-2, 16/11419-0)
RODRIGO N. SILVA; HEITOR A. SILVEIRA; LUCIANA Y. ALMEIDA; CARLA N. B. COLTURATO; ALEXANDRE ELIAS TRIVELLATO; CASSIO E. SVERZUT; JORGE E. LEÓN. Carcinoma cuniculado gengival mimetizando um processo inflamatório/reativo. Jornal Brasileiro de Patologia e Medicina Laboratorial, v. 55, n. 5, p. 498-505, . (16/11419-0, 18/12734-2, 16/02713-2)
TEIXEIRA, LUCAS R.; ALMEIDA, LUCIANA Y.; SILVA, RODRIGO N.; MESQUITA, ANA T. M.; COLTURATO, CARLA B. N.; SILVEIRA, HEITOR A.; DUARTE, ANDRESSA; RIBEIRO-SILVA, ALFREDO; LEON, JORGE E.. Young and elderly oral squamous cell carcinoma patients present similar angiogenic profile and predominance of M2 macrophages: Comparative immunohistochemical study. HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK, v. 41, n. 12, p. 4111-4120, . (18/12734-2, 16/11419-0, 17/02502-4, 16/02713-2)
SILVEIRA, HEITOR ALBERGONI; ALMEID, LUCIANA YAMAMOTO; CARLOS, ROMAN; SILVAA, EVANIO VILELA; FERRISSE, TULIO MORANDIN; DUARTE, ANDRESSA; CARDOSO, SUZIENE CAROLINE SIVAILVA; POLANCO, XIOMARA BEATRIZ JIMENEZ; BUFALINO, ANDREIA; RIBEIRO-SILVA, ALFREDO; et al. Human papillomavirus co-infection and survival in oral and oropharyngeal squamous cell carcinoma: A study in 235 Brazilian patients. AURIS NASUS LARYNX, v. 49, n. 2, p. 13-pg., . (16/02713-2, 16/11419-0, 18/12734-2)

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