EDUARDO MAGALHAES REGO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
5 resultados
Resultados de Busca
Agora exibindo 1 - 5 de 5
- The Multikinase Inhibitor AD80 Induces Mitotic Catastrophe and Autophagy in Pancreatic Cancer Cells(2023) LIMA, Keli; MIRANDA, Livia Bassani Lins de; GARNIQUE, Anali Del Milagro Bernabe; ALMEIDA, Bruna Oliveira de; NASCIMENTO, Mariane Cristina do; ALCANTARA, Guilherme Augusto Sousa; MACHADO-SANTELLI, Glaucia Maria; REGO, Eduardo Magalhaes; MACHADO-NETO, Joao AgostinhoSimple Summary Pancreatic cancer is one of the most lethal human neoplasms, and its therapeutic repertoire remains limited. Advances in understanding the molecular complexity involved in the biology of the disease have paved the way for new therapeutic opportunities. AD80 is a multikinase inhibitor that inhibits S6K as well as RET, RAF, and SRC and displays antineoplastic effects in hematological and solid tumors. In the present study, we report the potential of AD80 as an antineoplastic agent for pancreatic cancer and the cellular and molecular changes induced by the drug. Significant advances in understanding the molecular complexity of the development and progression of pancreatic cancer have been made, but this disease is still considered one of the most lethal human cancers and needs new therapeutic options. In the present study, the antineoplastic effects of AD80, a multikinase inhibitor, were investigated in models of pancreatic cancer. AD80 reduced cell viability and clonogenicity and induced polyploidy in pancreatic cancer cells. At the molecular level, AD80 reduced RPS6 and histone H3 phosphorylation and induced & gamma;H2AX and PARP1 cleavage. Additionally, the drug markedly decreased AURKA phosphorylation and expression. In PANC-1 cells, AD80 strongly induced autophagic flux (consumption of LC3B and SQSTM1/p62). AD80 modulated 32 out of 84 autophagy-related genes and was associated with vacuole organization, macroautophagy, response to starvation, cellular response to nitrogen levels, and cellular response to extracellular stimulus. In 3D pancreatic cancer models, AD80 also effectively reduced growth independent of anchorage and cell viability. In summary, AD80 induces mitotic aberrations, DNA damage, autophagy, and apoptosis in pancreatic cancer cells. Our exploratory study establishes novel targets underlying the antineoplastic activity of the drug and provides insights into the development of therapeutic strategies for this disease.
- High ME1 Expression Is a Molecular Predictor of Post-Transplant Survival of Patients with Acute Myeloid Leukemia(2023) ROJAS, Cesar Alexander Ortiz; COSTA-NETO, Abel; PEREIRA-MARTINS, Diego A.; LE, Duy Minh; STERNADT, Dominique; WEINHAEUSER, Isabel; HULS, Gerwin; SCHURINGA, Jan Jacob; REGO, Eduardo MagalhaesSimple Summary Acute myeloid leukemia (AML) is a blood cancer caused by genetic aberrations acquired by bone marrow progenitor cells, impeding healthy hematopoiesis. While AML is a heterogenous disease and variable parameters can impact AML prognosis, the options for treatments remain limited. The first line of treatment continues to be chemotherapy, usually followed by a hematopoietic stem cell transplant (HSCT) obtained from a compatible healthy donor. Of those transplanted patients, only about 50-60% will be long-term survivors. Consequently, the identification of markers that may predict the resulting HSCT outcome is a medical need. To address this issue, we applied different mathematical models at diagnosis to the transcriptome of AML patients who were treated with standard chemotherapy and then subjected to HSCT, in order to uncover genes associated with the clinical outcome post-transplant. By doing so we identified the ME1 gene, whereby high expression of ME1 was associated with worse prognosis. Furthermore, ME1 expression was correlated with energetic processes related to oxidative phosphorylation. Our study reveals that ME1 is an important biomarker and a potential therapeutic target. Several laboratory and clinical variables have been reported to be associated with the outcome of intensive chemotherapy for acute myeloid leukemia (AML), but only a few have been tested in the context of hematopoietic stem cell transplant (HSCT). This study aimed to identify genes whose expression of AML at diagnosis were associated with survival after HSCT. For this purpose, three publicly available adult AML cohorts (TCGA, BeatAML, and HOVON), whose patients were treated with intensive chemotherapy and then subjected to allogeneic or autologous HSCT, were included in this study. After whole transcriptome analysis, we identified ME1 as the only gene whose high expression was associated with shorter survival in patients subjected to HSCT. In addition, the inclusion of ME1 expression was able to improve the European LeukemiaNet risk stratification. Pathways related to lipid biosynthesis, mainly fatty acids, and cholesterol were positively correlated with ME1 expression. Furthermore, ME1 expression was associated with an M2 macrophage-enriched microenvironment, mature AML blasts hierarchy, and oxidative phosphorylation metabolism. Therefore, ME1 expression can be used as biomarker of poor response to HSCT in AML.
- Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia(2020) WEINHAUSER, Isabel; PEREIRA-MARTINS, Diego A.; ORTIZ, Cesar; SILVEIRA, Douglas R.; SIMOES, Luise A. A.; BIANCO, Thiago M.; ARAUJO, Cleide L.; KOURY, Luisa C.; MELO, Raul A. M.; BITTENCOURT, Rosane I.; PAGNANO, Katia; PASQUINI, Ricardo; NUNES, Elenaide C.; FAGUNDES, Evandro M.; GLORIA, Ana B.; KERBAUY, Fabio; CHAUFFAILLE, Maria de Lourdes; KEATING, Armand; TALLMAN, Martin S.; RIBEIRO, Raul C.; DILLON, Richard; GANSER, Arnold; LOWENBERG, Bob; VALK, Peter; LO-COCO, Francesco; SANZ, Miguel A.; BERLINER, Nancy; AMMATUNA, Emanuele; LUCENA-ARAUJO, Antonio R.; SCHURINGA, Jan Jacob; REGO, Eduardo M.Simple Summary In solid tumors, the altered expression of embryonic genes such as the SLIT-ROBO family has been associated with poor prognosis, while little is known about their role in acute myeloid leukemia (AML). Previous studies reported frequent hypermethylation of SLIT2 mediated by the methyltransferase enzyme EZH2 and more recently the PML protein, which are commonly found to be aberrantly expressed in AML. Here, we aim to assess retrospectively the clinical relevance of the SLIT2 gene in acute promyelocytic leukemia, a homogenous subtype of AML. We demonstrated that reduced SLIT2 expression was associated with high leukocyte counts and reduced overall survival in different APL cohorts. STLI2 treatment decreased APL growth, while SLIT2 knockdown accelerated cell cycle progression and proliferation. Finally, reduced expression of SLIT2 in murine APL blasts resulted in fatal leukemia associated with increased leukocyte counts in vivo. These findings demonstrate that SLIT2 can be considered as a prognostic marker in APL, and a potential candidate for clinical studies of a more heterogeneous disease, such as AML. The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2(high) transcript levels were associated with cell cycle arrest, while SLIT2(low) APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92-0.97; p < 0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated.
- Systematic Review of Available CAR-T Cell Trials around the World(2022) BARROS, Luciana Rodrigues Carvalho; COUTO, Samuel Campanelli Freitas; SANTURIO, Daniela da Silva; PAIXAO, Emanuelle Arantes; CARDOSO, Fernanda; SILVA, Viviane Jennifer da; KLINGER, Paulo; RIBEIRO, Paula do Amaral Costa; ROS, Felipe Augusto; OLIVEIRA, Theo Gremen Mimary; REGO, Eduardo Magalhaes; RAMOS, Rodrigo Nalio; ROCHA, VandersonSimple Summary CAR-T cells are genetically modified T cells that are reprogrammed to specifically eliminate cancer cells. Due to its clinical success to treat certain hematological malignancies, novel approaches to improve CAR-T cell-based therapies are being explored. This systematic review gives a worldwide overview of clinical trials evaluating new CAR-T cell therapies against different types of cancers, detailing the latest trends in CAR-T cell development. In this systematic review, we foresee what could be the approved scenario in the next few years for CAR-T cell therapies directed against hematological and solid tumor malignancies. China and the USA are the leading regions in numbers of clinical studies involving CAR-T. Hematological antigens CD19 and BCMA are the most targeted, followed by mesothelin, GPC3, CEA, MUC1, HER2, and EGFR for solid tumors. Most CAR constructs are second-generation, although third and fourth generations are being largely explored. Moreover, the benefit of combining CAR-T treatment with immune checkpoint inhibitors and other drugs is also being assessed. Data regarding product formulation and administration, such as cell phenotype, transfection technique, and cell dosage, are scarce and could not be retrieved. Better tracking of trials' status and results on the ClinicalTrials.gov database should aid in a more concise and general view of the ongoing clinical trials involving CAR-T cell therapy.
- How to Manage Philadelphia-Positive Acute Lymphoblastic Leukemia in Resource-Constrained Settings(2023) SILVA, Wellington; REGO, Eduardo; MARTELLI, Alberto MariaSimple Summary Remarkable strides have been performed in the treatment of adults diagnosed with Philadelphia-positive lymphoblastic leukemia (Ph+ ALL) through the integration of newer-generation tyrosine-kinase inhibitors and monoclonal antibodies. However, it is crucial to acknowledge that most medical centers worldwide lack access to these therapies. As a result, primary strategies employed for curing this disease continue to rely on a combination of chemotherapy and allogeneic stem-cell transplantation. Additionally, the scarcity of comprehensive literature makes it particularly challenging to provide straightforward treatment recommendations. In this narrative review, our aim is to offer a real-world perspective on the monitoring and management of Ph+ ALL patients, with an emphasis on less-resourced scenarios.Abstract Recent studies have indicated that more than half of adult patients newly diagnosed with Ph+ ALL can now achieve a cure. However, determining the most suitable protocol for less-resourced settings can be challenging. In these situations, we must consider the potential for treatment toxicity and limited access to newer agents and alloSCT facilities. Currently, it is advisable to use less intensive induction regimens for Ph+ ALL. These regimens can achieve high rates of complete remission while causing fewer induction deaths. For consolidation therapy, chemotherapy should remain relatively intensive, with careful monitoring of the BCR-ABL1 molecular transcript and minimal residual disease. AlloSCT may be considered, especially for patients who do not achieve complete molecular remission or have high-risk genetic abnormalities, such as IKZF1-plus. If there is a loss of molecular response, it is essential to screen patients for ABL mutations and, ideally, change the TKI therapy. The T315I mutation is the most common mechanism for disease resistance, being targetable to ponatinib. Blinatumomab, a bispecific antibody, has shown significant synergy with TKIs in treating this disease. It serves as an excellent salvage therapy, aside from achieving outstanding results when incorporated into the frontline.