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1.
Biochim Biophys Acta Mol Cell Res ; 1871(7): 119801, 2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-39038611

RESUMO

Cancer-associated fibroblasts (CAFs) are key contributors to ovarian cancer (OC) progression and therapeutic resistance through dysregulation of the extracellular matrix (ECM). CAFs are a heterogenous population derived from different cell types through activation and reprogramming. Current studies rely on uncharacterized heterogenous primary CAFs or normal fibroblasts that fail to recapitulate CAF-like tumor behavior. Here, we present that conditioned media from ovarian cancer lines leads to an increase in the activated state of fibroblasts demonstrated by functional assays and up-regulation of known CAF-related genes and ECM pathways. Phenotypic and functional characterization demonstrated that the conditioned CAFs expressed a CAF-like phenotype, strengthened proliferation, secretory, contractility, and ECM remodeling properties when compared to resting normal fibroblasts, consistent with an activated fibroblast status. Moreover, conditioned CAFs significantly enhanced drug resistance and tumor progression. Critically, the conditioned CAFs resemble a transcriptional signature with involvement of ECM remodeling. The present study provides mechanistic and functional insights about the activation and reprogramming of CAFs in the ovarian tumor microenvironment mediated by non-vesicular paracrine signaling. Moreover, it provides a translational based approach to reprogram normal fibroblasts from both uterine and ovarian origin into CAFs using tumor-derived conditioned media. Using these resources, further development of therapeutics that possess potentiality and specificity towards CAF/ECM-mediated chemoresistance in OC are further warranted.

2.
bioRxiv ; 2024 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-38853974

RESUMO

Introduction: The majority of ovarian cancer (OC) patients receiving standard of care chemotherapy develop chemoresistance within 5 years. The tumor microenvironment (TME) is a dynamic and influential player in disease progression and therapeutic response. However, there is a lack of models that allow us to elucidate the compartmentalized nature of TME in a controllable, yet physiologically relevant manner and its critical role in modulating drug resistance. Methods: We developed a 3D microvascularized multiniche tumor-on-a-chip formed by five chambers (central cancer chamber, flanked by two lateral stromal chambers and two external circulation chambers) to recapitulate OC-TME compartmentalization and study its influence on drug resistance. Stromal chambers included endothelial cells alone or cocultured with normal fibroblasts or cancer-associated fibroblasts (CAF). Results: The tumor-on-a-chip recapitulated spatial TME compartmentalization including vessel-like structure, stromal-mediated extracellular matrix (ECM) remodeling, generation of oxygen gradients, and delayed drug diffusion/penetration from the circulation chamber towards the cancer chamber. The cancer chamber mimicked metastasis-like migration and increased drug resistance to carboplatin/paclitaxel treatment in the presence of CAF when compared to normal fibroblasts. CAF-mediated drug resistance was rescued by ECM targeted therapy. Critically, these results demonstrate that cellular crosstalk recreation and spatial organization through compartmentalization are essential to determining the effect of the compartmentalized OC-TME on drug resistance. Conclusions: Our results present a functionally characterized microvascularized multiniche tumor-on-a-chip able to recapitulate TME compartmentalization influencing drug resistance. This technology holds the potential to guide the design of more effective and targeted therapeutic strategies to overcome chemoresistance in OC.

3.
Front Oncol ; 14: 1394648, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38756667

RESUMO

Background: The measurement of minimal residual disease (MRD) by multiparametric flow cytometry (MFC) before hematopoietic stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) is a powerful prognostic factor. The interaction of pretransplant MRD and the conditioning intensity has not yet been clarified. Objective: The aim of this study is to analyze the transplant outcomes of patients with AML who underwent HSCT in complete remission (CR), comparing patients with positive MRD (MRD+) and negative MRD (MRD-) before HSCT, and the interaction between conditioning intensity and pre-HSCT MRD. Study design: We retrospectively analyzed the transplant outcomes of 118 patients with AML who underwent HSCT in CR in a single institution, comparing patients with MRD+ and MRD- before HSCT using a cutoff of 0.1% on MFC, and the interaction between conditioning intensity and pre-HSCT MRD. Results: Patients with MRD+ before HSCT had a significantly worse 2-year (2y) event-free survival (EFS) (56.5% vs. 32.0%, p = 0.018) than MRD- patients, due to a higher cumulative incidence of relapse (CIR) at 2 years (49.0% vs. 18.0%, p = 0.002), with no differences in transplant-related mortality (TRM) (2y-TRM, 19.0% and 25.0%, respectively, p = 0.588). In the analysis stratified by conditioning intensity, in patients who received MAC, those with MRD- before HSCT had better EFS (p = 0.009) and overall survival (OS) (p = 0.070) due to lower CIR (p = 0.004) than MRD+ patients. On the other hand, the survival was similar in reduced intensity conditioning (RIC) patients regardless of the MRD status. Conclusions: Patients with MRD+ before HSCT have worse outcomes than MRD- patients. In patients who received MAC, MRD- patients have better EFS and OS due to lower CIR than MRD+ patients, probably because they represent a more chemo-sensitive group. However, among RIC patients, results were similar regardless of the MRD status.

4.
bioRxiv ; 2023 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-37873479

RESUMO

Cancer-associated fibroblasts (CAFs) are key contributors to ovarian cancer (OC) progression and therapeutic resistance through dysregulation of the extracellular matrix (ECM). CAFs are a heterogenous population derived from different cell types through activation and reprogramming. Current studies rely on uncharacterized heterogenous primary CAFs or normal fibroblasts that fail to recapitulate CAF-like tumor behavior. Here, we present a translatable-based approach for the reprogramming of normal uterine fibroblasts into ovarian CAFs using ovarian tumor-derived conditioned media to establish two well-characterized ovarian conditioned CAF lines. Phenotypic and functional characterization demonstrated that the conditioned CAFs expressed a CAF-like phenotype, strengthened proliferation, secretory, contractility, and ECM remodeling properties when compared to resting normal fibroblasts, consistent with an activated fibroblast status. Moreover, conditioned CAFs significantly enhanced drug resistance and tumor progression and resembled a CAF-like subtype associated with worse prognosis. The present study provides a reproducible, cost-effective, and clinically relevant protocol to reprogram normal fibroblasts into CAFs using tumor-derived conditioned media. Using these resources, further development of therapeutics that possess potentiality and specificity towards CAF-mediated chemoresistance in OC are further warranted.

5.
Blood Cancer J ; 13(1): 77, 2023 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-37173322

RESUMO

Next-Generation Sequencing is needed for the accurate genetic risk stratification of acute myeloid leukemia according to European LeukemiaNet (ELN) guidelines. We validated and compared the 2022 ELN risk classification in a real-life cohort of 546 intensively and 379 non-intensively treated patients. Among fit patients, those aged ≥65 years old showed worse OS than younger regardless risk classification. Compared with the 2017 classification, 14.5% of fit patients changed the risk with the 2022 classification, increasing the high-risk group from 44.3% to 51.8%. 3.7% and 0.9% FLT3-ITD mutated patients were removed from the favorable and adverse 2017 categories respectively to 2022 intermediate risk group. We suggest that midostaurin therapy could be a predictor for 3 years OS (85.2% with vs. 54.8% without midostaurin, P = 0.04). Forty-seven (8.6%) patients from the 2017 intermediate group were assigned to the 2022 adverse-risk group as they harbored myelodysplasia (MDS)-related mutations. Patients with one MDS-related mutation did not reach median OS, while patients with ≥2 mutations had 13.6 months median OS (P = 0.002). Patients with TP53 ± complex karyotype or inv(3) had a dismal prognosis (7.1 months median OS). We validate the prognostic utility of the 2022 ELN classification in a real-life setting providing supportive evidences to improve risk stratification guidelines.


Assuntos
Leucemia Mieloide Aguda , Nucleofosmina , Humanos , Idoso , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Prognóstico , Fatores de Risco , Mutação
6.
Clin Transl Med ; 13(4): e1217, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37029785

RESUMO

BACKGROUND: The dismal prognosis of advanced ovarian cancer calls for the development of novel therapies to improve disease outcome. In this regard, we set out to discover new molecular entities and to assess the preclinical effectiveness of their targeting. METHODS: Cell lines, mice and human ovarian cancer samples were used. Proteome profiling of human phosphokinases, in silico genomic analyses, genetic (shRNA and CRISPR/Cas9) and pharmacological strategies as well as an ex vivo human preclinical model were performed. RESULTS: We identified WNK1 as a highly phosphorylated protein in ovarian cancer and found that its activation or high expression had a negative impact on patients' survival. Genomic analyses showed amplification of WNK1 in human ovarian tumours. Mechanistically, we demonstrate that WNK1 exerted its action through the MEK5-ERK5 signalling module in ovarian cancer. Loss of function, genetic or pharmacological experiments, demonstrated anti-proliferative and anti-tumoural effects of the targeting of the WNK1-MEK5-ERK5 route. Additional studies showed that this pathway modulated the anti-tumoural properties of the MEK1/2 inhibitor trametinib. Thus, treatment with trametinib activated the WNK1-MEK5-ERK5 route, raising the possibility that this effect may limit the therapeutic benefit of ERK1/2 targeting in ovarian cancer. Moreover, in different experimental settings, including an ex vivo patient-derived model consisting of ovarian cancer cells cultured with autologous patient sera, we show that inhibition of WNK1 or MEK5 increased the anti-proliferative and anti-tumour efficacy of trametinib. CONCLUSIONS: The present study uncovers the participation of WNK1-MEK5-ERK5 axis in ovarian cancer pathophysiology, opening the possibility of acting on this pathway with therapeutic purposes. Another important finding of the present study was the activation of that signalling axis by trametinib, bypassing the anti-tumoural efficacy of this drug. That fact should be considered in the context of the use of trametinib in ovarian cancer.


Assuntos
MAP Quinase Quinase 5 , Neoplasias Ovarianas , Humanos , Animais , Camundongos , Feminino , MAP Quinase Quinase 5/genética , MAP Quinase Quinase 5/metabolismo , Sistema de Sinalização das MAP Quinases , Transdução de Sinais , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Proteína Quinase 1 Deficiente de Lisina WNK/genética , Proteína Quinase 1 Deficiente de Lisina WNK/metabolismo
7.
Hematol Oncol ; 41(4): 753-761, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37081742

RESUMO

Secondary acute myeloid leukemia (s-AML) patients have a poor prognosis and currently the only curative therapy is allogeneic stem-cell transplant (HSCT). However, we do not yet know whether transplantation is sufficient to reverse the poor prognosis compared to de novo AML patients. We analyzed survival after HSCT comparing a cohort of 58 patients with s-AML versus 52 de novo patients who were transplanted between 2012 and 2020. Patients with s-AML had worse event-free survival (EFS) (p = 0.001) and overall survival (OS) (p < 0.001) compared to de novo AML due to an increased risk of relapse (p = 0.06) and non-relapse mortality (p = 0.03). The main difference in survival was observed in patients who achieved complete remission (CR) before HSCT (EFS p = 0.002 OS and <0.001), regardless minimal residual disease (MRD) by |multiparametric flow cytometry cohorts. In patients transplanted with active disease (AD), the prognosis was adverse in both s-AML and de novo AML groups (EFS p = 0.869 and OS p = 0.930). After excluding patients with AD, we stratified the cohort according to conditioning intensity, noticing that s-AML who received MAC had comparable outcomes to de novo AML, but the survival differences remained among reduce intensity conditioning group. In conclusion, transplanted s-AML patients have worse survival among patients in CR before HSCT, regardless of MRD level by flow cytometry compared to de novo AML. MAC patients had similar outcomes irrespective of leukemia ontogeny.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Segunda Neoplasia Primária , Humanos , Neoplasia Residual , Citometria de Fluxo , Transplante Homólogo , Leucemia Mieloide Aguda/terapia , Prognóstico , Estudos Retrospectivos
8.
Cancers (Basel) ; 15(2)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36672386

RESUMO

Next-Generation Sequencing (NGS) implementation to perform accurate diagnosis in acute myeloid leukemia (AML) represents a major challenge for molecular laboratories in terms of specialization, standardization, costs and logistical support. In this context, the PETHEMA cooperative group has established the first nationwide diagnostic network of seven reference laboratories to provide standardized NGS studies for AML patients. Cross-validation (CV) rounds are regularly performed to ensure the quality of NGS studies and to keep updated clinically relevant genes recommended for NGS study. The molecular characterization of 2856 samples (1631 derived from the NGS-AML project; NCT03311815) with standardized NGS of consensus genes (ABL1, ASXL1, BRAF, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, GATA2, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1 and WT1) showed 97% of patients having at least one mutation. The mutational profile was highly variable according to moment of disease, age and sex, and several co-occurring and exclusion relations were detected. Molecular testing based on NGS allowed accurate diagnosis and reliable prognosis stratification of 954 AML patients according to new genomic classification proposed by Tazi et al. Novel molecular subgroups, such as mutated WT1 and mutations in at least two myelodysplasia-related genes, have been associated with an adverse prognosis in our cohort. In this way, the PETHEMA cooperative group efficiently provides an extensive molecular characterization for AML diagnosis and risk stratification, ensuring technical quality and equity in access to NGS studies.

9.
J Mol Biol ; 435(2): 167895, 2023 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-36463932

RESUMO

Micrograph comparison remains useful in bioscience. This technology provides researchers with a quick snapshot of experimental conditions. But sometimes a two- condition comparison relies on researchers' eyes to draw conclusions. Our Bioimage Analysis, Statistic, and Comparison (BASIN) software provides an objective and reproducible comparison leveraging inferential statistics to bridge image data with other modalities. Users have access to machine learning-based object segmentation. BASIN provides several data points such as images' object counts, intensities, and areas. Hypothesis testing may also be performed. To improve BASIN's accessibility, we implemented it using R Shiny and provided both an online and offline version. We used BASIN to process 498 image pairs involving five bioscience topics. Our framework supported either direct claims or extrapolations 57% of the time. Analysis results were manually curated to determine BASIN's accuracy which was shown to be 78%. Additionally, each BASIN version's initial release shows an average 82% FAIR compliance score.


Assuntos
Biofilmes , Disciplinas das Ciências Biológicas , Processamento de Imagem Assistida por Computador , Aprendizado de Máquina , Software , Processamento de Imagem Assistida por Computador/métodos , Fluxo de Trabalho , Conjuntos de Dados como Assunto , Disciplinas das Ciências Biológicas/métodos
10.
Cancers (Basel) ; 14(23)2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36497281

RESUMO

FLT3−ITD results in a poor prognosis in terms of overall survival (OS) and relapse-free survival (RFS) in acute myeloid leukemia (AML). However, the prognostic usefulness of the allelic ratio (AR) to select post-remission therapy remains controversial. Our study focuses on the prognostic impact of FLT3−ITD and its ratio in a series of 2901 adult patients treated intensively in the pre-FLT3 inhibitor era and reported in the PETHEMA registry. A total of 579 of these patients (20%) harbored FLT3−ITD mutations. In multivariate analyses, patients with an FLT3−ITD allele ratio (AR) of >0.5 showed a lower complete remission (CR rate) and OS (HR 1.47, p = 0.009), while AR > 0.8 was associated with poorer RFS (HR 2.1; p < 0.001). Among NPM1/FLT3−ITD-mutated patients, median OS gradually decreased according to FLT3−ITD status and ratio (34.3 months FLT3−ITD-negative, 25.3 months up to 0.25, 14.5 months up to 0.5, and 10 months ≥ 0.5, p < 0.001). Post-remission allogeneic transplant (allo-HSCT) resulted in better OS and RFS as compared to auto-HSCT in NPM1/FLT3−ITD-mutated AML regardless of pre-established AR cutoff (≤0.5 vs. >0.5). Using the maximally selected log-rank statistics, we established an optimal cutoff of FLT3−ITD AR of 0.44 for OS, and 0.8 for RFS. We analyzed the OS and RFS according to FLT3−ITD status in all patients, and we found that the group of FLT3−ITD-positive patients with AR < 0.44 had similar 5-year OS after allo-HSCT or auto-HSCT (52% and 41%, respectively, p = 0.86), but worse RFS after auto-HSCT (p = 0.01). Among patients with FLT3−ITD AR > 0.44, allo-HSCT was superior to auto-HSCT in terms of OS and RFS. This study provides more evidence for a better characterization of patients with AML harboring FLT3−ITD mutations.

11.
Dis Markers ; 2022: 3132941, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36051360

RESUMO

Gemtuzumab ozogamicin (GO) is a conjugate of a monoclonal antibody and calicheamicin, which has been reapproved for the treatment of acute myeloid leukemia (AML). AML patients with the CD33 rs12459419 CC genotype might benefit from the addition of GO to intensive treatment in contrast to patients with CT/TT genotypes. Nevertheless, contradictory results have been reported. We sought to shed light on the prediction of GO response in AML patients with rs12459419 polymorphism who were treated with GO in the consolidation (n = 70) or reinduction (n = 20) phase. The frequency distribution of the rs12459419 polymorphism in the complete cohort of patients was 44.4% (n = 40), 50% (n = 45), and 5.6% (n = 5) for CC, CT, and TT genotypes, respectively. Regarding the patients treated with GO for consolidation, we performed a Kaplan-Meier analysis of overall survival and relapse-free survival according to the rs12459419 polymorphism (CC vs. CT/TT patients) and genetic risk using the European Leukemia Net (ELN) 2010 risk score. We also carried out a Cox regression analysis for the prediction of overall survival, with age and ELN 2010 as covariates. We found no statistical significance in the univariate or multivariate analysis. Additionally, we performed a global Kaplan-Meier analysis for the patients treated with GO for reinduction and did not find significant differences; however, our cohort was too small to draw any conclusion from this analysis. The use of GO in consolidation treatment is included in the approval of the compound; however, evidence regarding its efficacy in this setting is lacking. Rs12459419 polymorphism could help in the selection of patients who might benefit from GO. Regrettably, in our cohort, the rs12459419 polymorphism does not seem to be an adequate tool for the selection of patients who might benefit from the addition of GO in consolidation cycles.


Assuntos
Aminoglicosídeos , Leucemia Mieloide Aguda , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico , Aminoglicosídeos/uso terapêutico , Anticorpos Monoclonais Humanizados/genética , Gemtuzumab/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Polimorfismo de Nucleotídeo Único , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética
12.
Cancers (Basel) ; 14(7)2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-35406526

RESUMO

This study investigates the effects of a dual selective Class I histone deacetylase (HDAC)/lysine-specific histone demethylase 1A (LSD1) inhibitor known as 4SC-202 (Domatinostat) on tumor growth and metastasis in a highly metastatic murine model of Triple Negative Breast Cancer (TNBC). 4SC-202 is cytotoxic and cytostatic to the TNBC murine cell line 4T1 and the human TNBC cell line MDA-MB-231; the drug does not kill the normal breast epithelial cell line MCF10A. Furthermore, 4SC-202 reduces cancer cell migration. In vivo studies conducted in the syngeneic 4T1 model, which closely mimics human TNBC in terms of sites of metastasis, reveal reduced tumor burden and lung metastasis. The mechanism of action of 4SC-202 may involve effects on cancer stem cells (CSC) which can self-renew and form metastatic lesions. Approximately 5% of the total 4T1 cell population grown in three-dimensional scaffolds had a distinct CD44high/CD24low CSC profile which decreased after treatment. Bulk transcriptome (RNA) sequencing analyses of 4T1 tumors reveal changes in metastasis-related pathways in 4SC-202-treated tumors, including changes to expression levels of genes implicated in cell migration and cell motility. In summary, 4SC-202 treatment of tumors from a highly metastatic murine model of TNBC reduces metastasis and warrants further preclinical studies.

13.
Biomolecules ; 12(2)2022 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-35204717

RESUMO

Leukemia Inhibitory Factor (LIF) is a member of the IL-6 cytokine family and is expressed in almost every tissue type within the body. Although LIF was named for its ability to induce differentiation of myeloid leukemia cells, studies of LIF in additional diseases and solid tumor types have shown that it has the potential to contribute to many other pathologies. Exploring the roles of LIF in normal physiology and non-cancer pathologies can give important insights into how it may be dysregulated within cancers, and the possible effects of this dysregulation. Within various cancer types, LIF expression has been linked to hallmarks of cancer, such as proliferation, metastasis, and chemoresistance, as well as overall patient survival. The mechanisms behind these effects of LIF are not well understood and can differ between different tissue types. In fact, research has shown that while LIF may promote malignancy progression in some solid tumors, it can have anti-neoplastic effects in others. This review will summarize current knowledge of how LIF expression impacts cellular function and dysfunction to help reveal new adjuvant treatment options for cancer patients, while also revealing potential adverse effects of treatments targeting LIF signaling.


Assuntos
Leucemia , Neoplasias , Humanos , Fator Inibidor de Leucemia/metabolismo , Transdução de Sinais
14.
Sci Rep ; 11(1): 19343, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34588522

RESUMO

Cancer patients undergo detrimental toxicities and ineffective treatments especially in the relapsed setting, due to failed treatment attempts. The development of a tool that predicts the clinical response of individual patients to therapy is greatly desired. We have developed a novel patient-derived 3D tissue engineered bone marrow (3DTEBM) technology that closely recapitulate the pathophysiological conditions in the bone marrow and allows ex vivo proliferation of tumor cells of hematologic malignancies. In this study, we used the 3DTEBM to predict the clinical response of individual multiple myeloma (MM) patients to different therapeutic regimens. We found that while no correlation was observed between in vitro efficacy in classic 2D culture systems of drugs used for MM with their clinical efficacious concentration, the efficacious concentration in the 3DTEBM were directly correlated. Furthermore, the 3DTEBM model retrospectively predicted the clinical response to different treatment regimens in 89% of the MM patient cohort. These results demonstrated that the 3DTEBM is a feasible platform which can predict MM clinical responses with high accuracy and within a clinically actionable time frame. Utilization of this technology to predict drug efficacy and the likelihood of treatment failure could significantly improve patient care and treatment in many ways, particularly in the relapsed and refractory setting. Future studies are needed to validate the 3DTEBM model as a tool for predicting clinical efficacy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Medula Óssea/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Técnicas de Cultura de Tecidos/métodos , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/patologia , Projetos Piloto , Cultura Primária de Células , Engenharia Tecidual , Resultado do Tratamento , Células Tumorais Cultivadas
15.
Leuk Lymphoma ; 62(10): 2457-2465, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33993837

RESUMO

Chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL) are hematological malignancies that remain incurable despite novel treatments. In order to improve current treatments and clinical efficacy, there remains a need for more complex in vitro models that mimic the intricate human leukemic microenvironment. This study aimed to use 3D tissue engineered plasma cultures (3DTEPC) derived from CML, AML and CLL patients to promote proliferation of leukemic cells for use as a drug screening tool for treatment. 3DTEPC supported the growth of primary CML, AML and CLL cells and also induced significantly more drug resistance in CML, AML and CLL cell lines compared to 2D. The 3DTEPC created a more physiologically relevant environment for leukemia cell proliferation, provided a reliable model for growing leukemia patient samples, and serves as a relevant tool for drug screening and personalized medicine.


Assuntos
Leucemia Linfocítica Crônica de Células B , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide Aguda , Proliferação de Células , Resistência a Medicamentos , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Microambiente Tumoral
16.
Transplant Cell Ther ; 27(4): 311.e1-311.e10, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33836871

RESUMO

Acute myeloid leukemia (AML) with intermediate risk cytogenetics (IRcyto) comprises a variety of biological entities with distinct mutational landscapes that translate into differential risks of relapse and prognosis. Optimal postremission therapy choice in this heterogeneous patient population is currently unsettled. In the current study, we compared outcomes in IRcyto AML recipients of autologous (autoSCT) (n = 312) or allogeneic stem cell transplantation (alloSCT) (n = 279) in first complete remission (CR1). Molecular risk was defined based on CEBPA, NPM1, and FLT3-ITD mutational status, per European LeukemiaNet 2017 criteria. Five-year overall survival (OS) in patients with favorable molecular risk (FRmol) was 62% (95% confidence interval [CI], 50-72) after autoSCT and 66% (95% CI, 41-83) after matched sibling donor (MSD) alloSCT (P = .68). For patients of intermediate molecular risk (IRmol), MSD alloSCT was associated with lower cumulative incidence of relapse (P < .001), as well as with increased nonrelapse mortality (P = .01), as compared to autoSCT. The 5-year OS was 47% (95% CI, 34-58) after autoSCT and 70% (95% CI, 59-79) after MSD alloSCT (P = .02) in this patient subgroup. In a propensity-score matched IRmol subcohort (n = 106), MSD alloSCT was associated with superior leukemia-free survival (hazard ratio [HR] 0.33, P = .004) and increased OS in patients alive 1 year after transplantation (HR 0.20, P = .004). These results indicate that, within IRcyto AML in CR1, autoSCT may be a valid option for FRmol patients, whereas MSD alloSCT should be the preferred postremission strategy in IRmol patients.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Análise Citogenética , Humanos , Leucemia Mieloide Aguda/genética , Nucleofosmina , Indução de Remissão , Transplante Homólogo
19.
Haematologica ; 106(12): 3079-3089, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33179471

RESUMO

Next-Generation Sequencing has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia. However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. To overcome this challenge, the PETHEMA group established a nationwide network of reference laboratories aimed to deliver molecular results in the clinics. We report the technical cross-validation results for next-generation sequencing panel genes during the standardization process and the clinical validation in 823 samples of 751 patients with newly diagnosed or refractory/relapse acute myeloid leukemia. Two cross-validation rounds were performed in seven nationwide reference laboratories in order to reach a consensus regarding quality metrics criteria and variant reporting. In the pre-standardization cross-validation round, an overall concordance of 60.98% was obtained with a great variability in selected genes and conditions across laboratories. After consensus of relevant genes and optimization of quality parameters the overall concordance rose to 85.57% in the second cross-validation round. We show that a diagnostic network with harmonized next-generation sequencing analysis and reporting in seven experienced laboratories is feasible in the context of a scientific group. This cooperative nationwide strategy provides advanced molecular diagnostic for acute myeloid leukemia patients of the PETHEMA group.


Assuntos
Leucemia Mieloide Aguda , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , Recidiva
20.
Nat Commun ; 11(1): 6037, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33247158

RESUMO

Drug resistance and dose-limiting toxicities are significant barriers for treatment of multiple myeloma (MM). Bone marrow microenvironment (BMME) plays a major role in drug resistance in MM. Drug delivery with targeted nanoparticles have been shown to improve specificity and efficacy and reduce toxicity. We aim to improve treatments for MM by (1) using nanoparticle delivery to enhance efficacy and reduce toxicity; (2) targeting the tumor-associated endothelium for specific delivery of the cargo to the tumor area, and (3) synchronizing the delivery of chemotherapy (bortezomib; BTZ) and BMME-disrupting agents (ROCK inhibitor) to overcome BMME-induced drug resistance. We find that targeting the BMME with P-selectin glycoprotein ligand-1 (PSGL-1)-targeted BTZ and ROCK inhibitor-loaded liposomes is more effective than free drugs, non-targeted liposomes, and single-agent controls and reduces severe BTZ-associated side effects. These results support the use of PSGL-1-targeted multi-drug and even non-targeted liposomal BTZ formulations for the enhancement of patient outcome in MM.


Assuntos
Bortezomib/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Nanopartículas/química , Inibidores de Proteínas Quinases/uso terapêutico , Microambiente Tumoral , Quinases Associadas a rho/antagonistas & inibidores , Amidas/farmacologia , Amidas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Bortezomib/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipossomos , Glicoproteínas de Membrana/metabolismo , Camundongos , Selectina-P/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral , Microambiente Tumoral/efeitos dos fármacos , Quinases Associadas a rho/metabolismo , Quinases da Família src/metabolismo
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