Identification of biomarkers and possible therapeutical targets in B-cell lymphoproliferative disorders

• Grant number: 10/17668-6
• Support Opportunities: Research Projects - Thematic Grants
• Start date: January 01, 2012
• End date: December 31, 2017
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Gisele Wally Braga Colleoni
• Grantee: Gisele Wally Braga Colleoni
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Pesquisadores principais: Mihoko Yamamoto
• Associated scholarship(s): 17/17101-5 - WEE1 gene relevance and its inhibition effect on Myeloma Multiple cancer stem cell survival, BP.IC; 15/23983-5 - Isolation and characterization of cancer stem-cells from bone marrow samples of newly diagnosed patients with multiple myeloma, BP.IC; 14/23093-7 - Histopathologic and immunophenotypical characterization of diffuse large B cell lymphoma of the elderly and correlation with microRNAs expression profile, BP.IC; + associated scholarships 14/10578-2 - Expression of angiogenesis-related microRNAs in serum samples of pacients with non-Hodgkin diffuse large B-cell lymphoma, at diagnosis and at the moment of recurrence, BP.IC; 12/23494-6 - Expression of JAK/STAT pathway genes using the Real Time Quantitative PCR array technique in multiple myeloma cell lines, before and after the use of potential inhibitors of the pathway, BP.IC; 12/23496-9 - Characterization of possible clonal origin and gene expression profile of human stromal cells derived from bone marrow of patients with multiple myeloma, BP.IC; 12/24614-5 - Immunophenotypic characterization and analysis of gene expression profiling of Cancer stem cell in multiple Myeloma, with focus on identification of potential therapeutic target, BP.IC; 10/19231-4 - IDENTIFICATION OF DIFFUSE LARGE B CELL LYMPHOMA SUBTYPES DEFINED BY THE EXPRESSION OF TUMOR STROMAL PROTEINS AND THEIR RELATIONSHIP WITH PROANGIOGENIC MICRORNAS, BP.IC; 10/16554-7 - Plasma membrane protein profiling in plasma cells, stromal cells and bone marrow microenvironment mononuclear cells in multiple myeloma patients using the ESI QTOF MS method., BP.PD; 10/19194-1 - EXPRESSION OF CANCER/TESTIS ANTIGENS AND POSSIBLE CORRELATION WITH GENES RELATED TO T REGULATORY AND TH17 LYMPHOCYTE SUBPOPULATIONS IN MULTIPLE MYELOMA, BP.IC - associated scholarships

Abstract

The main objective of this proposal is the development of studies that aggressively seek possible biomarkers and therapeutic targets four frequent B-cell lymphoproliferative disorders: multiple myeloma (MM), diffuse large B-cell lymphomas (DLBCL), mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). The subproject 1 aims at identifying mutations JAK/STAT pathway genes and possible targets for the use of inhibitors of tyrosine-quinases in MM. The subproject 2 is an offshoot of the work initiated during the Clinical Cancer Genome Project, trying to assess the correlation between cancer/ testis antigens, that are possible targets for immunotherapy in MM, and some of T lymphocyte sub- populations that can have key role in regulating the response of MM patients to this type of intervention. The subproject 3 is the unfolding of another work developed during the Clinical Cancer Genome Project and attempt to assess the role of two genes still not well explored in MM (P53CSV and HSP70), that may represent targets for this disease. In the subproject 4, analysis of proteins expressed in the membranes of plasma cells, stromal and mononuclear cells present in MM bone marrow microenviroment by ESI QTOF MS technique (electrospray ionization quadrupole time of flight mass spectrometry) would be helpful in the discovery of new therapeutic targets in MM, a still uncurable disease. In the subproject 5, we explore the role of microRNAs (miRNAs) involved in the process of angiogenesis in DLBCL to assess their potential as therapeutic targets. In the sub-project 6, we will evaluate the profile of miRNAs in a newly described Epstein-Barr virus related diffuse large B-cell lymphoma of elderly, characterized by unfavourable clinical evolution. The subproject 7 will evaluate the frequency of monoclonal B-cell lymphocytosis (MBL) in pure Japanese descendent population resident in Brazil. These findings may be helpful in understanding the relationship between MBL and CLL and also clarify the pathogenesis and natural history of CLL. In the subproject 8 we will evaluate if halofuginone cytotoxicity in mantle cell lymphoma (MCL) is mediated by inhibition of Akt and NF-ºB signaling pathways. This hypothesis, if confirmed, could elucidate the mechanisms of antitumoral action of halofuginone and substantiate its rational combination with other classes of drugs as a new therapeutic strategy for MCL. Keywords: multiple myeloma; non-Hodgkin's lymphomas; chronic lymphocytic leukemia; diagnosis; treatment; prognosis; translational research; gene expression; Epstein-Barr virus; microRNA; angiogenesis; proteomics; molecular markers; potential therapeutic targets. (AU)

Scientific publications

(17)

(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)

BRAGA, WALTER M. T.; DA SILVA, BRUNA R.; ALVES, VERUSKA L. F.; BORTOLUZO, ADRIANA B.; ATANACKOVIC, DJORDJE; COLLEONI, GISELE W. B.. Is there any relationship between gene expression of tumor antigens and CD4(+) T cells in multiple myeloma?. Immunotherapy, v. 6, n. 5, p. 569-575, MAY 2014. (10/17668-6)

DE ANDRADE, TATHIANA AZEVEDO; EVANGELISTA, ADRIANE FEIJO; FROES CAMPOS, ANTONIO HUGO; POLES, WAGNER AUGUSTO; BORGES, NATALIA MORAIS; COUTINHO CAMILLO, CLAUDIA MALHEIROS; SOARES, FERNANDO AUGUSTO; VASSALLO, JOSE; PAES, ROBERTO PINTO; ZERBINI, MARIA CLAUDIA; et al. A microRNA signature profile in EBV+ diffuse large B-cell lymphoma of the elderly. ONCOTARGET, v. 5, n. 23, p. 11813-11826, DEC 15 2014. (10/17668-6)

TOBIAS BRAGA, WALTER MOISES; DA SILVA, BRUNA RAPHAELI; DE CARVALHO, ANA CAROLINA; MAEKAWA, YUMI H.; BORTOLUZZO, ADRIANA BRUSCATO; RIZZATTI, EDGAR GIL; ATANACKOVIC, DJORDJE; BRAGA COLLEONI, GISELE WALLY. FOXP3 and CTLA4 overexpression in multiple myeloma bone marrow as a sign of accumulation of CD4(+) T regulatory cells. CANCER IMMUNOLOGY IMMUNOTHERAPY, v. 63, n. 11, p. 1189-1197, NOV 2014. (10/17668-6)

FOOK-ALVES, VERUSKA L.; DE OLIVEIRA, MARIANA BLEKER; ZANATTA, DANIELA B.; STRAUSS, BRYAN E.; COLLEONI, GISELE W. B.. TP53 Regulated Inhibitor of Apoptosis 1 (TRIAP1) stable silencing increases late apoptosis by upregulation of caspase 9 and APAF1 in RPMI8226 multiple myeloma cell line. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v. 1862, n. 6, p. 1105-1110, JUN 2016. (10/17668-6)

DE OLIVEIRA, MARIANA B.; FOOK-ALVES, VERUSKA L.; EUGENIO, ANGELA I. P.; FERNANDO, RODRIGO C.; SANSON, LUIZ FELIPE G.; DE CARVALHO, MARIANA F.; BRAGA, WALTER M. T.; DAVIES, FAITH E.; COLLEONI, GISELE W. B.. Anti-myeloma effects of ruxolitinib combined with bortezomib and lenalidomide: A rationale for JAK/STAT pathway inhibition in myeloma patients. Cancer Letters, v. 403, p. 206-215, SEP 10 2017. (10/17668-6)

BORGES, NATALIA M.; DO VALE ELIAS, MARCELA; FOOK-ALVES, VERUSKA L.; ANDRADE, TATHIANA A.; DE CONTI, MARINA LOURENCO; MACEDO, MARIANA PETACCIA; BEGNAMI, MARIA DIRLEI; CAMPOS, ANTONIO HUGO J. F. M.; ETTO, LEINA YUKARI; BORTOLUZZO, ADRIANA BRUSCATO; et al. Angiomirs expression profiling in diffuse large B-Cell lymphoma. ONCOTARGET, v. 7, n. 4, p. 4806-4816, JAN 26 2016. (10/17668-6)

DE FARIA-MOSS, MARIANE; YAMAMOTO, MIHOKO; ARRAIS-RODRIGUES, CELSO; CRIADO, IGNACIO; GOMES, CAIO PEREZ; CHAUFFAILLE, MARIA DE LOURDES; GONCALVES, MATHEUS VESCOVI; KIMURA, ELIZA; KOULIERIS, EFSTATHIOS; BORGES, FABIO; et al. High frequency of chronic lymphocytic leukemia-like low-count monoclonal B-cell lymphocytosis in Japanese descendants living in Brazil. Haematologica, v. 105, n. 6, p. E298-E301, JUN 2020. (10/17668-6)

DE OLIVEIRA, MARIANA BLEKER; EUGENIO, ANGELA ISABEL; ALVES, VERUSKA LIA FOOK; ZANATTA, DANIELA; YAMAMOTO, MIHOKO; STRAUSS, BRYAN ERIC; COLLEONI, GISELE W. B.. Heat Shock Protein 70 Inhibitor, Alone or in Combination with Bortezomib, Prevented Plasmacytoma Development in Immunodeficient Mice Transplanted with Myeloma Cell Lines. Blood, v. 128, n. 22, p. 3-pg., 2016-12-02. (10/17668-6)

COTRIM GUERREIRO DA SILVA, ISMAEL DALE; DE CASTRO LEVATTI, ERICA VALADARES; PEDROSO, AMANDA PAULA; LOBO MARCHIONI, DIRCE MARIA; FERREIRA CARIOCA, ANTONIO AUGUSTO; BRAGA COLLEONI, GISELE WALLY. Biochemical phenotyping of multiple myeloma patients at diagnosis reveals a disorder of mitochondrial complexes I and II and a Hartnup-like disturbance as underlying conditions, also influencing different stages of the disease. SCIENTIFIC REPORTS, v. 10, n. 1, DEC 14 2020. (17/21801-2, 10/17668-6)

DE OLIVEIRA, MARIANA B.; SANSON, LUIZ F. G.; EUGENIO, ANGELA I. P.; BARBOSA-DANTAS, REBECCA S. S.; COLLEONI, GISELE W. B.. Stew in its Own Juice: Protein Homeostasis Machinery Inhibition Reduces Cell Viability in Multiple Myeloma Cell Lines. CURRENT MOLECULAR MEDICINE, v. 19, n. 2, p. 112-119, 2019. (10/17668-6)

PEREIRA EUGENIO, ANGELA ISABEL; FOOK-ALVES, VERUSKA LIA; DE OLIVEIRA, MARIANA BLEKER; FERNANDO, RODRIGO CARLINI; ZANATTA, DANIELA B.; STRAUSS, BRYAN ERIC; REGIS SILVA, MARIA REGINA; PORCIONATTO, MARIMELIA APARECIDA; BRAGA COLLEONI, GISELE WALLY. Proteasome and heat shock protein 70 (HSP70) inhibitors as therapeutic alternative in multiple myeloma. ONCOTARGET, v. 8, n. 70, p. 114698-114709, DEC 29 2017. (10/17668-6)

POLES, WAGNER A.; NISHI, ERIKA E.; DE OLIVEIRA, MARIANA B.; EUGENIO, ANGELA I. P.; DE ANDRADE, TATHIANA A.; CAMPOS, ANTONIO HUGO F. M.; DE CAMPOS, JR., RUY R.; VASSALLO, JOSE; ALVES, ANTONIO C.; NETO, CRISTOVAM SCAPULATEMPO; et al. Targeting the polarization of tumor-associated macrophages and modulating mir-155 expression might be a new approach to treat diffuse large B-cell lymphoma of the elderly. CANCER IMMUNOLOGY IMMUNOTHERAPY, v. 68, n. 2, p. 269-282, FEB 2019. (10/17668-6)

BARBOSA, REBECCA S. S.; DANTONIO, PAOLA M.; GUIMARAES, TAIS; DE OLIVEIRA, MARIANA B.; FOOK ALVES, VERUSKA L.; SANDES, ALEX FREIRE; FERNANDO, RODRIGO CARLINI; COLLEONI, GISELE W. B.. Sequential combination of bortezomib and WEE1 inhibitor, MK-1775, induced apoptosis in multiple myeloma cell lines. Biochemical and Biophysical Research Communications, v. 519, n. 3, p. 597-604, NOV 12 2019. (10/17668-6, 17/21801-2, 15/23983-5, 17/17101-5)

BORGES, N.; CONTI, M.; ANDRADE, T.; MACEDO, M.; BEGNAMI, M.; ALVES, A.; COLLEONI, G.. IDENTIFICATION OF DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) SUBTYPES DEFINED BY THE EXPRESSION OF STROMAL PROTEINS AND THEIR ASSOCIATION WITH MICRORNAS INVOLVED IN ANGIOGENESIS. Haematologica, v. 98, p. 2-pg., 2013-06-12. (10/17668-6)

ANDRADE, T.; EVANGELISTA, A.; BORGES, N.; JAMPIETRO, J.; MACEDO, M.; BEGNAMI, M.; ALVES, A.; COLLEONI, G.. SEVEN MICRORNAS DIFFERENTIATE PATIENTS WITH EBV-POSITIVE DIFFUSE LARGE B-CELL LYMPHOMA OF THE ELDERLY FROM DIFFUSE LARGE B-CELL LYMPHOMA NOT OTHERWISE SPECIFIED: A MICRORNA SIGNATURE PROFILE PROPOSAL. Haematologica, v. 98, p. 1-pg., 2013-06-12. (10/17668-6)

DE OLIVEIRA, MARIANA BLEKER; ALVES, VERUSKA LIA FOOK; EUGENIO, ANGELA ISABEL; FERNANDO, RODRIGO CARLINI; YAMAMOTO, MIHOKO; COLLEONI, GISELE W. B.. In Vitro JAK1/2 Inhibition, in Association with Bortezomib and Lenalidomide, Is Comparable with Bortezomib, Lenalidomide and Dexametasone: An Alternative for Multiple Myeloma Patients with JAK2 overexpression?. Blood, v. 128, n. 22, p. 3-pg., 2016-12-02. (10/17668-6)

DE OLIVEIRA, MARIANA BLEKER; DANTONIO, PAOLA MARINO; ALVES, VERUSKA LIA FOOK; FERNANDO, RODRIGO CARLINI; TEIXEIRA, DANIELA; BASSO, ALEXANDRE; YAMAMOTO, MIHOKO; COLLEONI, GISELE W. B.. Multiple Myeloma Cancer Stem Cells: Immunophenotypic and Functional Characterization, Gene Expression Profiling and Therapeutic Targets. Blood, v. 128, n. 22, p. 5-pg., 2016-12-02. (15/23983-5, 10/17668-6)