Predictors of severity and new treatments for bone marrow neoplasias

• Grant number: 17/21801-2
• Support Opportunities: Research Projects - Thematic Grants
• Duration: April 01, 2019 - March 31, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Sara Teresinha Olalla Saad
• Grantee: Sara Teresinha Olalla Saad
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Pesquisadores principais:( Atuais ): Mary Ann Foglio
• Pesquisadores principais:( Anteriores ): Gisele Wally Braga Colleoni
• Associated researchers: Anamika Dhyani ; Bruno Deltreggia Benites ; Cristiane Okuda Torello ; Fernanda Marconi Roversi ; Fernando Vieira Pericole de Souza ; João Ernesto de Carvalho ; Mariana Lazarini ; Paula de Melo Campos ; Simone Cristina Olenscki Gilli
• Associated scholarship(s): 24/12896-3 - Transcriptome analysis of transgenic MDS mice using RNA-Seq to investigate the profile of signaling pathways altered by the action of polyphenolic compounds, BP.TT; 23/03765-0 - Investigation of the role of PDPN in the pathophysiology of coagulopathy in acute promyelocytic leukemia, BP.DR; 24/01052-9 - PREDICTORS OF SEVERITY AND NOVEL TREATMENTS FOR BONE MARROW NEOPLASMS / Zebrafish maintenance and assistance in in vivo experiment., BP.TT; + associated scholarships 23/14472-3 - EFFECTS OF PROLONGED TREATMENT WITH EPIGALLOCATECHIN-3-GALLATE IN AN ANIMAL MODEL OF MYELODYSPLASTIC SYNDROME", BP.IC; 23/05873-4 - Evaluation of signaling pathways, apoptosis and reactive oxygen species in an experimental model of myelodysplastic syndrome treated with artesunate, BP.IC; 22/05624-1 - Predictors of severity and new treatments for bone marrow neoplasias: evaluation of the potential as epigenetic modulators of quercetin, epigallocatechin-3-gallate, gallic acid, curcumin, artemisinin and derivatives in leukemias and MDSs, BP.PD; 21/05230-0 - Activity of WNT signaling pathway inhibitors in in vitro models, BP.DD; 21/06389-3 - Predictors of severity and new treatments for Bone Marrow Neoplasias/mechanisms by which quercetin, epigallocatechin 3-gallate, gallic acid, turmeric, artemisimna and derivatives shape epigenetic alterations and energetic metabolism in the myelodysplasia, BP.PD; 21/05132-9 - Severity predictors and new treatments for bone marrow neoplasms, BP.IC; 21/03320-2 - Avaliação de indivíduos com citopenia clonal de significado incerto, BP.IC; 20/09208-7 - Predictors of severity and new treatments for Bone Marrow Neoplasias, BP.PD; 20/10771-8 - Predictors of severity and new treatments for bone marrow neoplasias/medullary fibrosis in chronic myeloproliferative neoplasms: inflammation and niche, BP.IC; 20/04133-9 - Predictors of severity and new treatments for bone marrow neoplasias: mechanisms by which quercetin, epigallocatechin 3-gallate, gallic acid, turmeric, artemisimine and derivatives modulate epigenetic changes and energy metabolism in myelodysplasia, BP.PD; 20/05553-1 - Predictors of severity and new treatments for bone marrow neoplasias, BP.IC; 19/25247-5 - Study of inhibitory and antitumor activity of natural substance-associated MAPK and WNT inhibitors in in vitro models, BP.TT; 19/21849-0 - Evaluation of the Pterodon pubescens Benth., Arrabidaea chica Verlot and Bixa orellana fruit extracts association in healing and antiproliferative activities, BP.TT; 19/18560-9 - ARHGAP21 in angiogenesis, BP.PD; 19/20080-5 - Development of bioinformatics tools for analysis and visualization of proteomics and genomics data, BP.TT; 19/18410-7 - Evaluation of the association of fruit extracts of Pterodon pubescens Benth., Arrabidaea chica Verlot and Bixa orellana in healing, antinociceptive and anti-inflammatory activities, BP.IC; 19/12273-8 - Evaluation of the association of fruit extracts of Pterodon pubescens, Arrabidaea chica Verlot and Bixa orellana on healing and antiproliferative activities, BP.IC; 19/13920-7 - Standardization and optimization of commercial kit for diagnosis of rearrangements b2a2 and b3a2 of the gene BCR/ABL: discontinuation of tyrosine kinase inhibitor in good prognosis patients with chronic myeloid leukemia, BP.IC; 19/18529-4 - Basic training in cell biology techniques, BP.TT; 19/12689-0 - Medullary fibrosis in chronic myeloproliferative neoplasms: inflammation and niche, BP.TT; 15/18574-9 - Screening of mutations related to hereditary anemias using NGS-Targeted sequencing panel, BP.PD; 15/21164-7 - Analysis of the mechanisms by which polyphenols epigallocatechin 3 gallate and Quercetin modulate epigenetic alterations present in leukemias and myelodysplastic syndromes, BP.PD - associated scholarships

Abstract

Bone marrow neoplasias are aggressive disorders with low healing potential. As the incidence of cancer increases with age, a growing number of older individuals are receiving therapy for cancer and frequently in intensive modalities. As these older patients tend to present comorbidities, treatment decisions can often become difficult due to their fragile physical state which may affect therapy tolerability and efficiency against cancer. The toxicity related to the treatment and long periods of hospitalization, often required, have a profound impact upon the quality of life of these patients. However, most elderly individuals and family members consider quality of life a priority. Additionally, extended treatments deplete the financial resources of both public and private health systems, and the extra costs also deplete the family´s financial reserves. In light of the foregoing, the present study will address novel therapeutic forms and severity predictors which could aid in therapy decision taking of the following bone marrow neoplasias: acute myeloid leukemia (AML) myelodysplastic syndromes (MDS), multiple myeloma (MM) and primary myelofibrosis (PMF). These disorders have a common characteristic which is the fatal course of the disease and the lack of efficient therapeutic options, where bone marrow transplantation represents the only curative therapy or therapy capable of extending survival, despite not being indicated for older patients or those with many comorbidities. Therefore, a number of issues could be clarified by this study: * What would be the effect of natural products, which have been demonstrated to be inductor agents of cell death or cell cycle arrest, upon the treatment of these disorders? These compounds have a known action of inducing or inhibiting reactive oxygen species (ROS) and/or nitric oxide and can have a direct effect upon the induction of neoplasia cell death or modulate cell immunity.*Would elderly patients have a better survival and quality of life were they to be treated with less aggressive therapies with less side effects? *Could mesenchymal cells or metformin reduce bone marrow fibrosis? *Would dendritic cell vaccines for AML and MM patients in remission, be an alternative for reducing disease recurrence? *Could severity markers for the aforementioned disorders, identified in our previous studies, be the targets of specific therapies? *Would the production of universal in vitro platelets to improve the support therapy of these patients be possible? This choice of investigation is a result of our dissatisfaction in observing that most patients with bone marrow neoplastic disorders are not candidates for last-generation treatments. Furthermore, the lack of hospital beds and the impossibility of using high cost antibiotics and immunobiologicals in the unified public health system (SUS) point to the need of performing high level research to seek alternatives to enable us, in the short-term, to face the reality of many patients who have no access to clinical studies with new high cost drugs, not only in Brazil, but throughout the World. For this investigation, we will carry out pre-clinical trials, using leukemia, myelodysplastic and xenogeneic tumor animal models, and phase I and II clinical studies. We will further standardize the production method of universal platelets, to enable better support for patients with severe bone marrow failure in consequence of hematologic neoplasia. (AU)

Publicações científicas

(28)

(Referências obtidas automaticamente do Web of Science e do SciELO, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores)

DE PAIVA, PAULA P.; NUNES, JULIA H. B.; NONATO, FABIANA R.; RUIZ, ANA L. T. G.; ZAFRED, RAFAEL R. T.; SOUSA, ILZA M. O.; OKUBO, MARCIA Y.; KAWANO, DANIEL F.; MONTEIRO, PAULA A.; FOGLIO, MARY A.; et al. In Silico, In Vitro, and In Vivo Antitumor and Anti-Inflammatory Evaluation of a Standardized Alkaloid-Enriched Fraction Obtained fromBoehmeria caudataSw. Aerial Parts. Molecules, v. 25, n. 17, SEP 2020. (17/21801-2, 12/19661-4, 11/22458-3, 14/06636-7, 11/22457-7)

RAMOS, DEBORA FELICIA VIEIRA; MANCUSO, RUBIA ISLER; CONTIERI, BRUNA; DUARTE, ADRIANA; PAIVA, LUCIANA; CARRILHO, JEFERSON DE MELO; SAAD, SARA TERESINHA OLALLA; LAZARINI, MARIANA. Rac GTPases in acute myeloid leukemia cells: Expression profile and biological effects of pharmacological inhibition. Toxicology and Applied Pharmacology, v. 442, p. 12-pg., 2022-05-01. (17/19674-2, 17/21801-2)

BUENO, MAURA LIMA PEREIRA; SAAD, SARA TERESINHA OLALLA; ROVERSI, FERNANDA MARCONI. WNT5A in tumor development and progression: A comprehensive review. BIOMEDICINE & PHARMACOTHERAPY, v. 155, p. 18-pg., 2022-10-18. (19/25247-5, 17/21801-2, 21/05320-0)

DE PAIVA, PAULA P.; NUNES, JULIA H. B.; NONATO, FABIANA R.; RUIZ, ANA L. T. G.; ZAFRED, RAFAEL R. T.; SOUSA, ILZA M. O.; OKUBO, MARCIA Y.; KAWANO, DANIEL F.; MONTEIRO, PAULA A.; FOGLIO, MARY A.; et al. In Silico, In Vitro, and In Vivo Antitumor and Anti-Inflammatory Evaluation of a Standardized Alkaloid-Enriched Fraction Obtained fromBoehmeria caudataSw. Aerial Parts. Molecules, v. 25, n. 17, p. 20-pg., 2020-09-01. (12/19661-4, 17/21801-2, 11/22457-7, 11/22458-3, 14/06636-7)

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)

MANCUSO, I, R.; FOGLIO, M. A.; SAAD, S. T. OLALLA. Artemisinin-type drugs for the treatment of hematological malignancies. Cancer Chemotherapy and Pharmacology, v. 87, n. 1, NOV 2020. (17/21801-2, 16/18384-8, 14/16008-3)

AZAMBUJA, JULIANA HOFSTATTER; MANCUSO, RUBIA ISLER; DELLA VIA, FERNANDA ISABEL; TORELLO, CRISTIANE OKUDA; SAAD, SARA TERESINHA OLALLA. rotective effect of green tea and epigallocatechin-3-gallate in a LPS-induced systemic inflammation mode. JOURNAL OF NUTRITIONAL BIOCHEMISTRY, v. 101, MAR 2022. (17/21801-2)

MANCUSO, RUBIA ISLER; AZAMBUJA, JULIANA HOFSTATTER; OLALLA SAAD, SARA TERESINHA. Artesunate strongly modulates myeloid and regulatory T cells to prevent LPS-induced systemic inflammation. BIOMEDICINE & PHARMACOTHERAPY, v. 143, NOV 2021. (17/21801-2)

GALVAO, FABIO; ZANONI, CAMILA TATIANA; MOREIRA, MARCOS MELLO; PASCHOAL, ILMA APARECIDA; OLALLA SAAD, SARA TERESINHA. Effects of home-based inspiratory muscle training on sickle cell disease (SCD) patients. Hematology, Transfusion and Cell Therapy, v. 43, n. 4, p. 443-452, OCT-DEC 2021. (17/21801-2, 11/51959-0)

LAZARINI, MARIANA; ASSIS-MENDONCA, GUILHERME ROSSI; MACHADO-NETO, JOAO AGOSTINHO; LATUF-FILHO, PAULO; BEZERRA, STEPHANIA MARTINS; VIEIRA, KARLA PRISCILA; SAAD, SARA TERESINHA OLALLA. Silencing of ARHGAP21, a Rho GTPase activating protein (RhoGAP), reduces the growth of prostate cancer xenografts in NOD/SCID mice. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1870, n. 4, p. 4-pg., 2023-02-17. (17/19674-2, 21/14630-2, 17/21801-2)

BUENO, M. L. P.; FOGLIO, M.; SAAD, S. T. O.; ROVERSI, F. MARCONI. Tocotrienol exerts on-target malignant activity against leukemia. MOLECULAR BIOLOGY OF THE CELL, v. 34, n. 2, p. 2-pg., 2023-02-01. (17/21801-2, 21/05320-0, 19/25247-5)

MACHADO JUNIOR, ROGERIO JOSE; CAMILLI, JULIA C.; BASTING, ROSANNA TARKANY; WIZIACKI ZAGO, PATRICIA MARIA; DE OLIVEIRA SOUSA, ILZA MARIA; BUGLIO, KAIO EDUARDO; RUIZ, ANA LUCIA T. G.; NOGUEIRA CARVALHO, PAULO ROBERTO; DE CARVALHO, JOAO ERNESTO; SAAD, SARA T. O.; et al. Cytoprotective effect of Fridericia chica (Bonpl.) LG Lohmann extract associated with geranylgeraniol enriched-fraction from Bixa orellana L. on epithelial cells treated with bisphosphonate. NATURAL PRODUCT RESEARCH, v. N/A, p. 6-pg., 2022-10-04. (17/21801-2)

BERNUSSO, VANESSA ALINE; VIEIRA, KARLA P.; DUARTE, ADRIANA S. S.; LESCANO, CAROLINE HONAISER; MONICA, FABIOLA ZAKIA; VICENTE, CRISTINA PONTES; DE PAULA, ERICH VINICIUS; OLALLA SAAD, SARA TERESINHA; LAZARINI, MARIANA. eficiency of ARHGAP21 alters megakaryocytic cell lineage responses and enhances platelet hemostatic functio. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1868, n. 6, MAY 2021. (17/21801-2, 13/13022-2, 17/19674-2)

BENITES, BRUNO DELTREGGIA; ALVAREZ, MARISA CLAUDIA; OLALLA SAAD, SARA TERESINHA. Small Particles, Big Effects: The Interplay Between Exosomes and Dendritic Cells in Antitumor Immunity and Immunotherapy. CELLS, v. 8, n. 12, DEC 2019. (17/21801-2)

COTRIM GUERREIRO DA SILVA, ISMAEL DALE; LOBO MARCHIONI, DIRCE MARIA; FERREIRA CARIOCA, ANTONIO AUGUSTO; BUENO, VALQUIRIA; BRAGA COLLEONI, GISELE WALLY. May critical molecular cross-talk between indoleamine 2,3-dioxygenase (IDO) and arginase during human aging be targets for immunosenescence control?. IMMUNITY & AGEING, v. 18, n. 1, AUG 13 2021. (17/21801-2)

MANCUSO, RUBIA ISLER; OLALLA SAAD, SARA TERESINHA; AZAMBUJA, JULIANA HOFSTATTER. Artesunate Switches Monocytes to an Inflammatory Phenotype with the Ability to Kill Leukemic Cells. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 2, JAN 2021. (17/21801-2)

ROVERSI, FERNANDA MARCONI; PEREIRA BUENO, MAURA LIMA; DA SILVA, JULIETE APARECIDA FRANCISCO; ASSIS-MENDONCA, GUILHERME ROSSI; TORELLO, CRISTIANE OKUDA; SHIRAISHI, RODRIGO NATO; PERICOLE, FERNANDO VIERA; FERRO, KARLA PRISCILA; SILVA DUARTE, ADRIANA SANTOS; REGO, EDUARDO MAGALHAES; et al. Novel inhibitor of hematopoietic cell kinase as a potential therapeutic agent for acute myeloid leukemia. CANCER IMMUNOLOGY IMMUNOTHERAPY, v. N/A, p. 13-pg., 2022-01-18. (17/21801-2)

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)

PEREIRA BUENO, MAURA LIMA; ARTICO, LEONARDO; SANTOS DUARTE, ADRIANA SILVA; BASSO, AUDREY; YUNES, JOSE ANDRES; SAAD, SARA T. OLALLA; ROVERSI, FERNANDA MARCONI. Combined Inhibition of MCL1 By AZD5991 and BCL2/Bclxl By AZD4320 As Promising Strategies to Overcome Acute Leukemia Tumor Burden and Niche Chemoresistance. Blood, v. 140, p. 2-pg., 2022-11-15. (17/21801-2, 21/05320-0, 19/25247-5)

ROVERSI, FERNANDA MARCONI; PEREIRA BUENO, MAURA LIMA; BASSO, AUDREY; SANTOS DUARTE, ADRIANA SILVA; SILVA, JULIETE A. F.; OLALLA SAAD, SARA T.. HCK Inhibition Displays Antineoplastic Activity on Acute Leukemia and Promotes Immune Regulation of the Bone Marrow Tumor Microenvironment. Blood, v. 140, p. 2-pg., 2022-11-15. (17/21801-2, 21/05320-0, 19/25247-5)

COSTA MELO SVIDNICKI, MARIA CAROLINA; FERREIRA FILHO, MOISES ALVES; BRANDAO, MARCELO MENDES; DOS SANTOS, MARIELZA; DIAS, RENATA DE OLIVEIRA; TAVARES, RENATO SAMPAIO; ASSIS-MENDONCA, GUILHERME ROSSI; TRAINA, FABIOLA; OLALLA SAAD, SARA TERESINHA. New germline GATA1 variant in females with anemia and thrombocytopenia. BLOOD CELLS MOLECULES AND DISEASES, v. 88, MAY 2021. (17/21801-2, 15/18574-9, 11/51959-0)

BERNUSSO, VANESSA ALINE; VIEIRA, KARLA P.; DUARTE, ADRIANA S. S.; LESCANO, CAROLINE HONAISER; MONICA, FABIOLA ZAKIA; VICENTE, CRISTINA PONTES; DE PAULA, ERICH VINICIUS; OLALLA SAAD, SARA TERESINHA; LAZARINI, MARIANA. Deficiency of ARHGAP21 alters megakaryocytic cell lineage responses and enhances platelet hemostatic function. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1868, n. 6, p. 13-pg., 2021-03-25. (17/19674-2, 13/13022-2, 17/21801-2)

ADRIANA DA SILVA SANTOS DUARTE; AUDREY BASSO ZANGIROLAMI; IRENE SANTOS; FERNANDA SOARES NIEMANN; HELEN NAEMI HONMA; EMERSON CLAYTON AMARO; MAURÍCIO WESLEY PERROUD JR.; FERNANDO VIEIRA PERICOLE; SIMONE CRISTINA OLENSCKI GILLI; BRUNO DELTREGGIA BENITES; et al. Production of dendritic cell vaccines using different methods with equivalent results: Implications for emerging centers. Hematology, Transfusion and Cell Therapy, v. 46, n. 1, p. 30-35, 2024-05-27. (17/21801-2)

SHIRAISHI, RODRIGO N.; BOMBEIRO, ANDRE L.; CASTRO, TAMARA C. L.; DELLA VIA, FERNANDA I.; SANTOS, IRENE; REGO, EDUARDO M.; SAAD, SARA T. O.; TORELLO, CRISTIANE O.. PML/RARa leukemia induced murine model for immunotherapy evaluation. TRANSPLANT IMMUNOLOGY, v. 81, p. 14-pg., 2023-08-26. (13/21539-5, 17/21801-2, 11/51959-0)

TORELLO, CRISTIANE OKUDA; ALVAREZ, MARISA CLAUDIA; OLALLA SAAD, SARA T.. Polyphenolic Flavonoid Compound Quercetin Effects in the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndromes. Molecules, v. 26, n. 19, OCT 2021. (17/21801-2, 14/08939-7)

DELLA VIA, FERNANDA ISABEL; SHIRAISHI, RODRIGO NAOTO; SANTOS, IRENE; FERRO, KARLA PRISCILA; SALAZAR-TERREROS, MYRIAM JANETH; FRANCHI JUNIOR, GILBERTO CARLOS; REGO, EDUARDO MAGALHAES; OLALLA SAAD, SARA TERESINHA; TORELLO, CRISTIANE OKUDA. (-)-Epigallocatechin-3-gallate induces apoptosis and differentiation in leukaemia by targeting reactive oxygen species and PIN1. SCIENTIFIC REPORTS, v. 11, n. 1, APR 27 2021. (17/21801-2, 11/51959-0)

MARIANA FERREIRA PISSARRA; CRISTIANE OKUDA TORELLO; SARA TERESINHA OLALLA SAAD; MARIANA LAZARINI. Evaluation of different protocols for culturing mesenchymal stem cells derived from murine bone marrow. Hematology, Transfusion and Cell Therapy, v. 44, n. 4, p. 560-566, 2022-12-12. (17/21801-2, 17/19674-2)

ROVERSI, FERNANDA MARCONI; PEREIRA BUENO, MAURA LIMA; FRANCISCO DA SILVA, JULIETE APARECIDA; ASSIS-MENDONCA, GUILHERME ROSSI; OLALLA SAAD, SARA TERESINHA. Optimized multiplex immunofluorescence for the characterization of tumor immune microenvironment in neoplastic paraffin-preserved tissues. JOURNAL OF CELL COMMUNICATION AND SIGNALING, v. 17, n. 3, p. 11-pg., 2023-05-16. (17/21801-2, 21/05320-0, 19/25247-5)