Percorrer por autor "Almeida, António M."
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- Clinical-genomic profiling of MDS to inform allo-HCT: recommendations from an international panel on behalf of the EBMTPublication . Gurnari, Carmelo; Robin, Marie; Adès, Lionel; Aljurf, Mahmoud; Almeida, António M.; Duarte, Fernando Barroso; Bernard, Elsa; Cutler, Corey; Porta, Matteo Giovanni Della; Witte, Theo De; DeZern, Amy; Drozd-Sokolowska, Joanna; Duncavage, Eric; Fenaux, Pierre; Gagelmann, Nico; Garcia-Manero, Guillermo; Haferlach, Claudia; Haferlach, Torsten; Hasserjian, Robert; Hellström-Lindberg, Eva; Jacoby, Meagan; Kulasekararaj, Austin; Lindsley, R. Coleman; Maciejewski, Jaroslaw P.; Makishima, Hideki; Malcovati, Luca; Mittelman, Moshe; Myhre, Anders E.; Ogawa, Seishi; Onida, Francesco; Papaemmanuil, Elli; Passweg, Jakob; Platzbecker, Uwe; Pleyer, Lisa; Raj, Kavita; Santini, Valeria; Sureda, Anna; Tobiasson, Magnus; Voso, Maria Teresa; Yakoub-Agha, Ibrahim; Zeidan, Amer; Walter, Matthew; Kröger, Nicolaus; McLornan, Donal P.; Cazzola, MarioFor patients with myelodysplastic neoplasm/syndrome (MDS), allogeneic hematopoietic cell transplantation (allo-HCT) represents the only potentially curative treatment, capable of eradicating disease-related mutant hematopoietic cells and establishing normal donor hematopoiesis. Biologic-assignment clinical trials have indicated that in eligible patients, allo-HCT is associated with superior clinical outcomes compared with nontransplant therapy. However, this therapeutic option is only available to a subset of patients, and the outcome is influenced by multiple factors inherent to the patient, the MDS subtype, and the allo-HCT procedure itself. In 2017, the European Society for Blood and Marrow Transplantation (EBMT) published recommendations for allo-HCT in MDS to guide practical decision-making. In the contemporary era, genomic profiling has become routine clinical practice in many centers, and the most recent classification systems include MDS entities that are defined by genetic abnormalities. In particular, the molecular International Prognostic Scoring System offers more precise prognostication across all clinical end points and currently represents the standard tool for estimating patient survival in the absence of disease-modifying treatment. Evidence from multiple sources increasingly indicates that allo-HCT should be considered at the time of diagnosis in all eligible patients with MDS. Therefore, genomic profiling for somatic mutations and testing for germ line predisposition variants are integral to determining a patient's eligibility for transplantation. Although all patients with higher-risk MDS are potential candidates for immediate transplantation, a subset of those with lower-risk MDS may also derive benefit from this procedure at an earlier disease stage. Comprehensive recommendations on behalf of an expert international panel for clinical practice and future clinical studies of relevance are presented.
- Combination of elacridar with imatinib modulates resistance associated with drug efflux transporters in chronic myeloid leukemiaPublication . Alves, Raquel; Gonçalves, Ana Cristina; Jorge, Joana; Almeida, António M.; Sarmento-Ribeiro, Ana BelaMultidrug resistance (MDR) development has emerged as a complication that compromises the success of several chemotherapeutic agents. In chronic myeloid leukemia (CML), imatinib resistance has been associated with changes in BCR-ABL1 and intracellular drug concentration, controlled by SLC and ABC transporters. We evaluate the therapeutic potential of a P-glycoprotein and BCRP inhibitor, elacridar, in sensitive (K562 and LAMA-84) and imatinib-resistant (K562-RC and K562-RD) CML cell lines as monotherapy and combined with imatinib. Cell viability was analyzed by resazurin assay. Drug transporter activity, cell death, cell proliferation rate, and cell cycle distribution were analyzed by flow cytometry. Both resistant models presented an increased activity of BCRP and P-gP compared to K562 cells. Elacridar as monotherapy did not reach IC50 in any CML models but activated apoptosis without cytostatic effect. Nevertheless, the association of elacridar (250 nM) with imatinib overcomes resistance, re-sensitizing K562-RC and K562-RD cells with five and ten times lower imatinib concentrations, respectively. Drug combination induced apoptosis with increased cleaved-caspases-3, cleaved-PARP and DNA damage, reduced cell proliferation rate, and arrested CML cells in the S phase. These data suggest that elacridar combined with imatinib might represent a new therapeutic option for overcoming TKI resistance involving efflux transporters. View Full-Text
- Genetic variants in oxidative stress-related genes and their impact on prognosis and treatment response in chronic myeloid leukemia patientsPublication . Alves, Raquel; Ventura, Filipa; Jorge, Joana; Marques, Gilberto; Coucelo, Margarida; Diamond, Joana; Oliveiros, Bárbara; Pereira, Amélia; Freitas-Tavares, Paulo; Almeida, António M.; Gonçalves, Ana Cristina; Sarmento-Ribeiro, Ana BelaChronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the BCR::ABL1 fusion gene, which codifies the BCR-ABL protein with increased tyrosine kinase activity. Despite the clinical results for the outstanding tyrosine kinase inhibitors (TKIs), drug resistance is a problem in CML management. Genetic variants that alter redox homeostasis by changing antioxidant enzyme expression or activity may influence patient responses and could enhance patient stratification. We aimed to assess the association of SOD2, CAT GPX1, NRF2, and KEAP1 genetic variants with TKI response and disease prognosis. For this purpose, we genotyped the variants rs4880 (SOD2), rs1050450 (GPX1), rs1001179 (CAT), rs6721961, rs4893819, rs35652124, rs6706649, rs13001694 (NFE2L2), and rs113540846 (KEAP1) via PCR in 187 CML patients. Our results show that variants in genes related to oxidative stress influence the development and degree of TKI resistance (allele G and GG genotypes of GPX1 and CT genotype of NFE2L2 rs4893819), the appearance of mutations in the BCR::ABL1 gene (AG genotype of NFE2L2 rs13001694 and genetic profile GGCTTCCCGG of the NFE2L2/KEAP1 axis), disease evolution (AG genotype of SOD2 and CT genotype of NFE2L2 rs4893819), and overall survival (CC genotype of CAT and GG genotype of NFE2L2 rs13001694) of CML patients. Our study found that variants in oxidative stress-related genes impact treatment response and outcomes in CML.
- Genetic variants of ABC and SLC transporter genes and chronic myeloid leukaemia: impact on susceptibility and prognosisPublication . Alves, Raquel; Goncalves, Ana Cristina; Jorge, Joana; Marques, Gilberto; Ribeiro, André B.; Tenreiro, Rita; Coucelo, Margarida; Diamond, Joana; Oliveiros, Bárbara; Pereira, Amélia; Freitas-Tavares, Paulo; Almeida, António M.; Sarmento-Ribeiro, Ana BelaSolute carrier (SLC) and ATP-binding cassette (ABC) transporters comprise a variety of proteins expressed on cell membranes responsible for intrusion or extrusion of substrates, respectively, including nutrients, xenobiotics, and chemotherapeutic agents. These transporters mediate the cellular disposition of tyrosine kinase inhibitors (TKIs), and their genetic variants could affect its function, potentially predisposing patients to chronic myeloid leukaemia (CML) and modulating treatment response. We explored the impact of genetic variability (single nucleotide variants—SNVs) of drug transporter genes (ABCB1, ABCG2, SLC22A1, and SLC22A5) on CML susceptibility, drug response, and BCR-ABL1 mutation status. We genotyped 10 SNVs by tetra-primers-AMRS-PCR in 198 CML patients and 404 controls, and assessed their role in CML susceptibility and prognosis. We identified five SNVs associated with CML predisposition, with some variants increasing disease risk, including TT genotype ABCB1 (rs1045642), and others showing a protective effect (GG genotype SLC22A5 rs274558). We also observed different haplotypes and genotypic profiles associated with CML predisposition. Relating to drug response impact, we found that CML patients with the CC genotype (rs2231142 ABCG2) had an increased risk of TKI resistance (six-fold). Additionally, CML patients carrying the CG genotype (rs683369 SLC22A1) presented a 4.54-fold higher risk of BCR-ABL1 mutations. Our results suggest that drug transporters’ SNVs might be involved in CML susceptibility and TKI response, and predict the risk of BCR-ABL1 mutations, highlighting the impact that SNVs could have in therapeutic selection.
- MicroRNA signature refine response prediction in CMLPublication . Alves, Raquel; Gonçalves, Ana Cristina; Jorge, Joana; Marques, Gilberto; Luís, Dino; Ribeiro, André B.; Freitas-Tavares, Paulo; Oliveiros, Bárbara; Almeida, António M.; Sarmento-Ribeiro, Ana BelamicroRNAs (miRs) dysregulation have emerged as a crucial step in tumorigenesis, being related with cancer development, progression and response to treatment. In chronic myeloid leukaemia (CML), the resistance to tyrosine kinase inhibitors (TKI) is responsible for treatment failure and could be linked to changes in miRs expression. This work aimed to correlate the expression levels of 3 miRs, miR-21, miR-26b and miR-451, with response to TKI treatment in CML patients. miR-451 levels at diagnosis were significantly higher in patients with optimal response after 6 and 12 months of therapy. Conversely, patients without optimal response had highest levels of miR-21. miR-21 and miR-451 appear to be good biomarkers of response, able to predict optimal TKI responders (p < 0.05). Using the combined profile of both miRs, we create a predictive model of optimal response after one year of treatment. This study highlights the role of miR-21 and miR-451 expression levels at diagnosis in predicting which patients achieve the optimal response.
- Resistance to tyrosine kinase inhibitors in chronic myeloid leukemia — from molecular mechanisms to clinical relevancePublication . Alves, Raquel; Gonçalves, Ana Cristina; Rutella, Sergio; Almeida, António M.; Rivas, Javier De Las; Trougakos, Ioannis P.; Ribeiro, Ana Bela SarmentoResistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.