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1.
Hum Mol Genet ; 30(1): 72-77, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33450762

RESUMEN

Ocular pterygium-digital keloid dysplasia (OPDKD) presents in childhood with ingrowth of vascularized connective tissue on the cornea leading to severely reduced vision. Later the patients develop keloids on digits but are otherwise healthy. The overgrowth in OPDKD affects body parts that typically have lower temperature than 37°C. We present evidence that OPDKD is associated with a temperature sensitive, activating substitution, p.(Asn666Tyr), in PDGFRB. Phosphorylation levels of PDGFRB and downstream targets were higher in OPDKD fibroblasts at 37°C but were further greatly increased at the average corneal temperature of 32°C. This suggests that the substitution cause significant constitutive autoactivation mainly at lower temperature. In contrast, a different substitution in the same codon, p.(Asn666Ser), is associated with Penttinen type of premature aging syndrome. This devastating condition is characterized by widespread tissue degeneration, including pronounced chronic ulcers and osteolytic resorption in distal limbs. In Penttinen syndrome fibroblasts, equal and high levels of phosphorylated PDGFRB was present at both 32°C and 37°C. This indicates that this substitution causes severe constitutive autoactivation of PDGFRB regardless of temperature. In line with this, most downstream targets were not affected by lower temperature. However, STAT1, important for tissue wasting, did show further increased phosphorylation at 32°C. Temperature-dependent autoactivation offers an explanation to the strikingly different clinical outcomes of substitutions in the Asn666 codon of PDGFRB.


Asunto(s)
Acroosteólisis/genética , Conjuntiva/anomalías , Deformidades Congénitas de las Extremidades/genética , Progeria/genética , Pterigion/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Anomalías Cutáneas/genética , Acroosteólisis/diagnóstico por imagen , Acroosteólisis/patología , Adolescente , Adulto , Sustitución de Aminoácidos/genética , Niño , Preescolar , Conjuntiva/diagnóstico por imagen , Conjuntiva/patología , Femenino , Humanos , Lactante , Deformidades Congénitas de las Extremidades/diagnóstico por imagen , Deformidades Congénitas de las Extremidades/patología , Masculino , Mutación Missense/genética , Fenotipo , Fosforilación/genética , Progeria/diagnóstico por imagen , Progeria/patología , Pterigion/diagnóstico por imagen , Pterigion/patología , Anomalías Cutáneas/patología , Temperatura , Adulto Joven
2.
Cancer Immunol Immunother ; 72(7): 2357-2373, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36939854

RESUMEN

Metastatic castration-resistant prostate cancer (mCRPC) is an immunologically cold disease with dismal outcomes. Cryoablation destroys cancer tissue, releases tumor-associated antigens and creates a pro-inflammatory microenvironment, while dendritic cells (DCs) activate immune responses through processing of antigens. Immunotherapy combinations could enhance the anti-tumor efficacy. This open-label, single-arm, single-center phase I trial determined the safety and tolerability of combining cryoablation and autologous immature DC, without and with checkpoint inhibitors. Immune responses and clinical outcomes were evaluated. Patients with mCRPC, confirmed metastases and intact prostate gland were included. The first participants underwent prostate cryoablation with intratumoral injection of autologous DCs in a 3 + 3 design. In the second part, patients received cryoablation, the highest acceptable DC dose, and checkpoint inhibition with either ipilimumab or pembrolizumab. Sequentially collected information on adverse events, quality of life, blood values and images were analyzed by standard descriptive statistics. Neither dose-limiting toxicities nor adverse events > grade 3 were observed in the 18 participants. Results indicate antitumor activity through altered T cell receptor repertoires, and 33% durable (> 46 weeks) clinical benefit with median 40.7 months overall survival. Post-treatment pain and fatigue were associated with circulating tumor cell (CTC) presence at inclusion, while CTC responses correlated with clinical outcomes. This trial demonstrates that cryoimmunotherapy in mCRPC is safe and well tolerated, also for the highest DC dose (2.0 × 108) combined with checkpoint inhibitors. Further studies focusing on the biologic indications of antitumor activity and immune system activation could be considered through a phase II trial focusing on treatment responses and immunologic biomarkers.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Células Dendríticas , Ipilimumab/uso terapéutico , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/terapia , Calidad de Vida , Microambiente Tumoral
3.
J Biol Chem ; 296: 100179, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33303632

RESUMEN

Breakpoint Cluster Region-Abelson kinase (BCR-Abl) is a driver oncogene that causes chronic myeloid leukemia and a subset of acute lymphoid leukemias. Although tyrosine kinase inhibitors provide an effective treatment for these diseases, they generally do not kill leukemic stem cells (LSCs), the cancer-initiating cells that compete with normal hematopoietic stem cells for the bone marrow niche. New strategies to target cancers driven by BCR-Abl are therefore urgently needed. We performed a small molecule screen based on competition between isogenic untransformed cells and BCR-Abl-transformed cells and identified several compounds that selectively impair the fitness of BCR-Abl-transformed cells. Interestingly, systems-level analysis of one of these novel compounds, DJ34, revealed that it induced depletion of c-Myc and activation of p53. DJ34-mediated c-Myc depletion occurred in a wide range of tumor cell types, including lymphoma, lung, glioblastoma, breast cancer, and several forms of leukemia, with primary LSCs being particularly sensitive to DJ34. Further analyses revealed that DJ34 interferes with c-Myc synthesis at the level of transcription, and we provide data showing that DJ34 is a DNA intercalator and topoisomerase II inhibitor. Physiologically, DJ34 induced apoptosis, cell cycle arrest, and cell differentiation. Taken together, we have identified a novel compound that dually targets c-Myc and p53 in a wide variety of cancers, and with particularly strong activity against LSCs.


Asunto(s)
Antineoplásicos/farmacología , Competencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Antineoplásicos/química , Línea Celular Tumoral , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Bibliotecas de Moléculas Pequeñas/química
4.
J Transl Med ; 20(1): 225, 2022 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-35568909

RESUMEN

BACKGROUND: Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients. METHODS: In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient's tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like 'admissible' monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system. DISCUSSION: Precision oncology means to stratify treatment based on specific patient characteristics and the molecular profile of the tumor. Use of targeted drugs is currently restricted to specific biomarker-defined subgroups of patients according to their market authorization. However, other cancer patients might also benefit of treatment with these drugs if the same biomarker is present. The emerging technologies in molecular diagnostics are now being implemented in Norway and it is publicly reimbursed, thus more cancer patients will have a more comprehensive genomic profiling of their tumour. Patients with actionable genomic alterations in their tumour may have the possibility to try precision cancer drugs through IMPRESS-Norway, if standard treatment is no longer an option, and the drugs are available in the study. This might benefit some patients. In addition, it is a good example of a public-private collaboration to establish a national infrastructure for precision oncology. Trial registrations EudraCT: 2020-004414-35, registered 02/19/2021; ClinicalTrial.gov: NCT04817956, registered 03/26/2021.


Asunto(s)
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapéutico , Humanos , Oncología Médica , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisión , Estudios Prospectivos
5.
FASEB J ; 34(3): 3773-3791, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31945226

RESUMEN

Chronic myeloid leukemia (CML) is a stem cell disease of the bone marrow where mechanisms of inter-leukemic communication and cell-to-cell interactions are proposed to be important for optimal therapy response. Tunneling nanotubes (TNTs) are novel intercellular communication structures transporting different cargos with potential implications in therapy resistance. Here, we have investigated TNTs in CML cells and following treatment with the highly effective CML therapeutics tyrosine kinase inhibitors (TKIs) and interferon-α (IFNα). CML cells from chronic phase CML patients as well as the blast crisis phase cell lines, Kcl-22 and K562, formed few or no TNTs. Treatment with imatinib increased TNT formation in both Kcl-22 and K562 cells, while nilotinib or IFNα increased TNTs in Kcl-22 cells only where the TNT increase was associated with adherence to fibronectin-coated surfaces, altered morphology, and reduced movement involving ß1integrin. Ex vivo treated cells from chronic phase CML patients showed limited changes in TNT formation similarly to bone marrow cells from healthy individuals. Interestingly, in vivo nilotinib treatment in a Kcl-22 subcutaneous mouse model resulted in morphological changes and TNT-like structures in the tumor-derived Kcl-22 cells. Our results demonstrate that CML cells express low levels of TNTs, but CML therapeutics increase TNT formation in designated cell models indicating TNT functionality in bone marrow derived malignancies and their microenvironment.


Asunto(s)
Adhesión Celular/efectos de los fármacos , Interferón-alfa/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Comunicación Celular/efectos de los fármacos , Línea Celular Tumoral , Células Cultivadas , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Immunoblotting , Integrina beta1/metabolismo , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Ratones , Microscopía Electrónica de Rastreo , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Eur J Haematol ; 107(6): 617-623, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34418168

RESUMEN

OBJECTIVES: Treatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-α in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN-α (PegIFN-α) in combination with dasatinib (DAS) in CML-CP. METHODS: Forty patients with newly diagnosed CML-CP were given DAS upfront. After month 3 (M3) 15 µg/wk of PegIFN-α was added and increased to 25 µg/wk from M7 until M15. DAS treatment was continued and adverse events and BCR-ABL1 qRT-PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long-term data. RESULTS: After 5 years of follow-up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML-related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study. CONCLUSION: Initial addition of PegIFN-α to DAS shows good long-term efficacy without increased toxicity.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dasatinib/uso terapéutico , Interferón-alfa/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Adulto , Anciano , Dasatinib/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Interferón-alfa/administración & dosificación , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Resultado del Tratamiento , Adulto Joven
7.
Br J Cancer ; 121(7): 545-555, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31413318

RESUMEN

BACKGROUND: Resistance to temozolomide (TMZ) is due in part to enhanced DNA repair mediated by high expression of O6-methyl guanine DNA methyltransferase (MGMT) that is often characterised by unmethylated promoter. Here, we investigated pre-treatment of glioblastoma (GBM) cells with the 26S-proteasome inhibitor bortezomib (BTZ) as a strategy to interfere with MGMT expression and thus sensitise them to TMZ. METHODS: Cell lines and patient GBM-derived cells were examined in vitro, and the latter also implanted orthotopically into NOD-SCID C.B.-Igh-1b/lcrTac-Prkdc mice to assess efficacy and tolerability of BTZ and TMZ combination therapy. MGMT promoter methylation was determined using pyrosequencing and PCR, protein signalling utilised western blotting while drug biodistribution was examined by LC-MS/MS. Statistical analysis utilised Analysis of variance and the Kaplan-Meier method. RESULTS: Pre-treatment with BTZ prior to temozolomide killed chemoresistant GBM cells with unmethylated MGMT promoter through MGMT mRNA and protein depletion in vitro without affecting methylation. Chymotryptic activity was abolished, processing of NFkB/p65 to activated forms was reduced and corresponded with low MGMT levels. BTZ crossed the blood-brain barrier, diminished proteasome activity and significantly prolonged animal survival. CONCLUSION: BTZ chemosensitized resistant GBM cells, and the schedule may be amenable for temozolomide refractory patients with unmethylated MGMT promoter.


Asunto(s)
Antineoplásicos/administración & dosificación , Bortezomib/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Temozolomida/administración & dosificación , Animales , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/enzimología , Línea Celular Tumoral , Esquema de Medicación , Resistencia a Antineoplásicos/efectos de los fármacos , Glioblastoma/diagnóstico por imagen , Glioblastoma/enzimología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estimación de Kaplan-Meier , Metilación , Ratones , Ratones Endogámicos NOD , Ratones SCID , Trasplante de Neoplasias , O(6)-Metilguanina-ADN Metiltransferasa/efectos de los fármacos , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas , ARN Mensajero/metabolismo , Factor de Transcripción ReIA/metabolismo
9.
Cytometry A ; 95(7): 792-796, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30964237

RESUMEN

We describe here a simple and efficient antibody titration approach for cell-surface markers and intracellular cell signaling targets for mass cytometry. The iterative approach builds upon a well-characterized backbone panel of antibodies and analysis using bioinformatic tools such as SPADE. Healthy peripheral blood and bone marrow cells are stained with a pre-optimized "backbone" antibody panel in addition to the progressively diluted (titrated) antibodies. Clustering based on the backbone panel enables the titration of each antibody against a rich hematopoietic background and assures that nonspecific binding and signal spillover can be quantified accurately. Using a slightly expanded backbone panel, antibodies quantifying changes in transcription factors and phosphorylated antigens are titrated on ex vivo stimulated cells to optimize sensitivity and evaluate baseline expression. Based on this information, complex panels of antibodies can be thoroughly optimized for use on healthy whole blood and bone marrow and are easily adaptable to the investigation of samples from for example clinical studies. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.


Asunto(s)
Anticuerpos , Antígenos/inmunología , Citometría de Flujo/métodos , Anticuerpos/química , Células Sanguíneas/metabolismo , Células de la Médula Ósea/metabolismo , Análisis por Conglomerados , Biología Computacional , Humanos
12.
Br J Cancer ; 119(8): 1028-1035, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30318517

RESUMEN

BACKGROUND: In the prospective population-based Norwegian Mother and Child Cohort Study (MoBa), comprising 113 754 offspring, we investigated the association between parental exposure to "gasoline or exhaust", as a proxy for benzene exposure, and childhood leukaemia. METHODS: Around gestational week 17, mothers and fathers responded to a questionnaire on exposure to various agents during the last 6 months and 6 months  pre-conception, respectively. Benzene exposure was assessed through self-reported exposure to "gasoline or exhaust". Cases of childhood leukaemia (n = 70) were identified through linkage with the Cancer Registry of Norway. Risk was estimated by hazard ratios (HRs) with 95% confidence intervals (95%CI), comparing offspring from exposed and unexposed parents using a Cox regression model. RESULTS: Maternal exposure to "gasoline or exhaust" was associated with an increased risk of childhood leukaemia (HR = 2.59; 95%CI: 1.03, 6.48) and acute lymphatic leukaemia (HR = 2.71; 95%CI: 0.97, 7.58). There was an increasing risk for higher exposure (p value for trend = 0.032 and 0.027). The association did not change after adjustment for maternal smoking. CONCLUSION: In spite of rather few cases, the findings in this prospective study, with the exposure metric defined a priori, support previous observations relating maternal exposure to benzene from gasoline and other petroleum-derived sources and the subsequent development of childhood leukaemia in the offspring.


Asunto(s)
Benceno/toxicidad , Gasolina/toxicidad , Exposición Materna/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Emisiones de Vehículos/toxicidad , Femenino , Humanos , Masculino , Noruega/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inducido químicamente , Embarazo , Estudios Prospectivos , Encuestas y Cuestionarios , Emisiones de Vehículos/análisis
13.
Haematologica ; Online ahead of print2018 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-29748445

RESUMEN

Internal tandem duplications in the tyrosine kinase receptor FLT3 (FLT3-ITD) are among the most common lesions in acute myeloid leukemia and there exists a need for new forms of treatment. Using ex vivo drug sensitivity screening, we found that FLT3-ITD+ patient cells are particularly sensitive to HSP90 inhibitors. While it is well known that HSP90 is important for FLT3-ITD stability, we found that HSP90 family members play a much more complex role in FLT3-ITD signaling than previously appreciated. First, we found that FLT3-ITD activates the unfolded protein response, leading to increased expression of GRP94/HSP90B1. This results in activation of a nefarious feedback loop, in which GRP94 rewires FLT3-ITD signaling by binding and retaining FLT3-ITD in the endoplasmic reticulum, leading to aberrant activation of downstream signaling pathways and further inducing the unfolded protein response. Second, HSP90 family proteins protect FLT3-ITD+ acute myeloid leukemia cells against apoptosis by alleviating proteotoxic stress, and treatment with HSP90 inhibitors results in proteotoxic overload that triggers unfolded protein response-induced apoptosis. Importantly, leukemic stem cells are strongly dependent upon HSP90 for their survival, and the HSP90 inhibitor ganetespib causes leukemic stem cell exhaustion in patient-derived mouse xenograft models. Taken together, our study reveals a molecular basis for HSP90 addiction of FLT3-ITD+ acute myeloid leukemia cells and provides a rationale for including HSP90 inhibitors in the treatment regime for FLT3-ITD+ acute myeloid leukemia.

14.
BMC Cancer ; 18(1): 684, 2018 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-29940909

RESUMEN

BACKGROUND: Uterine serous carcinoma (USC) is a rare but aggressive subtype of endometrial carcinoma. Large-scale comprehensive efforts have resulted in an improved molecular understanding of its pathogenesis, and the p53 pathway has been proposed as a key player and is potentially targetable. Here we attempt to further portray the p53 pathway in USC by assessing p53 isoform expression. METHODS: We applied quantitative Real-Time PCRs (RT-qPCR) for expression analyses of total p53 mRNA as well as quantitative distinction of p53ß, p53γ, and the total mRNA of amino-terminal truncated Δ40p53 and Δ133p53 in a retrospective cohort of 37 patients with USC. TP53 mutation status was assessed by targeted massive parallel sequencing. Findings were correlated with clinical data. RESULTS: The p53 isoform expression landscape in USCs was heterogeneous and dominated by total Δ133p53, while the distinct p53ß and p53γ variants were found at much lower levels. The isoform expression profiles varied between samples, while their expression was independent of TP53 mutation status. We found high relative p53γ expression to be associated with reduced progression-free survival (PFS). CONCLUSIONS: This is the first indication that elevated p53γ expression is associated with reduced PFS in USC. This single-center study may offer some insight in the landscape of p53 isoform expression in USC, but further validation studies are crucial to understand the context-dependent and tissue-specific role of the p53 isoform network in gynecological cancer.


Asunto(s)
Cistadenocarcinoma Seroso/genética , Proteína p53 Supresora de Tumor/genética , Neoplasias Uterinas/genética , Anciano , Anciano de 80 o más Años , Cistadenocarcinoma Seroso/mortalidad , Femenino , Humanos , Persona de Mediana Edad , Mutación , Supervivencia sin Progresión , Isoformas de Proteínas/genética , ARN Mensajero/análisis , Estudios Retrospectivos , Proteína p53 Supresora de Tumor/fisiología , Neoplasias Uterinas/mortalidad
16.
Haematologica ; 102(8): 1361-1367, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28522574

RESUMEN

Monitoring of single cell signal transduction in leukemic cellular subsets has been proposed to provide deeper understanding of disease biology and prognosis, but has so far not been tested in a clinical trial of targeted therapy. We developed a complete mass cytometry analysis pipeline for characterization of intracellular signal transduction patterns in the major leukocyte subsets of chronic phase chronic myeloid leukemia. Changes in phosphorylated Bcr-Abl1 and the signaling pathways involved were readily identifiable in peripheral blood single cells already within three hours of the patient receiving oral nilotinib. The signal transduction profiles of healthy donors were clearly distinct from those of the patients at diagnosis. Furthermore, using principal component analysis, we could show that phosphorylated transcription factors STAT3 (Y705) and CREB (S133) within seven days reflected BCR-ABL1IS at three and six months. Analyses of peripheral blood cells longitudinally collected from patients in the ENEST1st clinical trial showed that single cell mass cytometry appears to be highly suitable for future investigations addressing tyrosine kinase inhibitor dosing and effect. (clinicaltrials.gov identifier: 01061177).


Asunto(s)
Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Pirimidinas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Análisis de la Célula Individual/métodos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Leucemia Mieloide de Fase Crónica/patología , Leucocitos/metabolismo , Fosforilación , Proteínas Tirosina Quinasas/uso terapéutico , Pirimidinas/farmacología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/inmunología
17.
BMC Cancer ; 17(1): 630, 2017 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-28877686

RESUMEN

BACKGROUND: Acute myeloid leukemia (AML) is an aggressive malignancy only cured by intensive therapy. However, many elderly and unfit patients cannot receive such treatment due to an unacceptable risk of treatment-related morbidity and mortality. Disease-stabilizing therapy is then the only possible strategy, one alternative being treatment based on all-trans retinoic acid (ATRA) combined with the histone deacetylase inhibitor valproic acid and possibly low-toxicity conventional chemotherapy. METHODS: Primary AML cells were derived from 43 patients included in two clinical studies of treatment based on ATRA, valproic acid and theophyllamine; low toxicity chemotherapy (low-dose cytarabine, hydroxyurea, 6-mercaptopurin) was also allowed. Pretreatment leukemic cells were analyzed by mutation profiling of 54 genes frequently mutated in myeloid malignancies and by global gene expression profiling before and during in vivo treatment. RESULTS: Patients were classified as responders and non-responders to the treatment, however response to treatment showed no significant associations with karyotype or mutational profiles. Significance analysis of microarray (SAM) showed that responders and non-responders significantly differed with regard to the expression of 179 different genes. The differentially expressed genes encoding proteins with a known function were further classified based on the PANTHER (protein annotation through evolutionary relationship) classification system. The identified genes encoded proteins that are involved in several important biological functions, but a main subset of the genes were important for transcriptional regulation. These pretherapy differences in gene expression were largely maintained during treatment. Our analyses of primary AML cells during in vivo treatment suggest that ATRA modulates HOX activity (i.e. decreased expression of HOXA3, HOXA4 and HOXA5 and their regulator PBX3), but altered function of DNA methyl transferase 3A (DNMT3A) and G-protein coupled receptor signaling may also contribute to the effect of the overall treatment. CONCLUSIONS: Responders and non-responders to AML stabilizing treatment based on ATRA and valproic acid differ in the pretreatment transcriptional regulation of their leukemic cells, and these differences may be important for the clinical effect of this treatment. TRIAL REGISTRATIONS: ClinicalTrials.gov no. NCT00175812 ; EudraCT no. 2004-001663-22, registered September 9, 2005 and ClinicalTrials.gov no. NCT00995332 ; EudraCT no. 2007-2007-001995-36, registered October 14, 2009.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biología Computacional/métodos , Femenino , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Humanos , Cariotipo , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Mutación , Pruebas de Farmacogenómica , Transcriptoma , Resultado del Tratamiento , Tretinoina/administración & dosificación , Ácido Valproico/administración & dosificación
18.
Cancer Immunol Immunother ; 64(3): 337-47, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25416072

RESUMEN

Invasive ovarian cancer is associated with poor outcome. The presence of infiltrating regulatory T-cells (Tregs) suppresses protective anti-tumor immune responses, and their accumulation into the tumor microenvironment correlates with reduced survival in ovarian cancer patients. Here, we conducted a detailed characterization of CD4(+) T-cells, CD8(+) T-cells and Treg subsets in the peripheral blood and malignant ascites fluid from seventeen patients with ovarian carcinoma of epithelial origin. Cell distribution, activation status and proliferation status were assessed by multi-color flow cytometry. In ascites fluid, a significant accumulation of CD8(+) cytotoxic T-cells and Tregs was observed compared to peripheral blood. Furthermore, a skewing toward the CD45RA(-) effector/memory compartment was observed in all T-cell subsets in the ascites fluid, but was most pronounced in the Treg population. Regulatory T-cells in the malignant ascites were more activated and had a higher proliferation rate compared to blood-derived cells from the same patient, and their number in ascites was positively correlated with the number of epithelial cells in effusion. In summary, we demonstrate an accumulation of activated CD4(+), CD8(+) and regulatory T-cells in the cancer microenvironment of ovarian carcinoma.


Asunto(s)
Ascitis/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Neoplasias Ováricas/inmunología , Linfocitos T Reguladores/inmunología , Ascitis/patología , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead/sangre , Factores de Transcripción Forkhead/inmunología , Humanos , Memoria Inmunológica , Leucocitos Mononucleares/inmunología , Activación de Linfocitos/inmunología , Neoplasias Ováricas/sangre , Neoplasias Ováricas/patología , Microambiente Tumoral/inmunología
19.
Blood ; 121(7): e34-42, 2013 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-23243270

RESUMEN

Antibodies play a fundamental role in diagnostic immunophenotyping of leukemias and in cell-targeting therapy. However, this versatility is not reflected in imaging diagnostics. In the present study, we labeled anti­human mAbs monochromatically against selected human myeloid markers expressed on acute myeloid leukemia (AML) cells, all with the same near-infrared fluorochrome. In a novel "multiplexing" strategy, we then combined these mAbs to overcome the limiting target-to-background ratio to image multiple xenografts of AML. Time-domain imaging was used to discriminate autofluorescence from the distinct fluorophore-conjugated antibodies. Imaging with multiplexed mAbs demonstrated superior imaging of AML to green fluorescent protein or bioluminescence and permitted evaluation of therapeutic efficacy with the standard combination of anthracycline and cytarabine in primary patient xenografts. Multiplexing mAbs against CD11b and CD11c provided surrogate imaging biomarkers of differentiation therapy in an acute promyelocytic leukemia model treated with all-trans retinoic acid combined with the histone-deacetylase inhibitor valproic acid. We present herein an optimizedapplication of multiplexed immunolabeling in vivo for optical imaging of AML cellxenografts that provides reproducible, highly accurate disease staging and monitoring of therapeutic effects.


Asunto(s)
Anticuerpos Monoclonales , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/inmunología , Animales , Antraciclinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno CD11b/metabolismo , Antígeno CD11c/metabolismo , Línea Celular Tumoral , Citarabina/administración & dosificación , Colorantes Fluorescentes , Proteínas Fluorescentes Verdes , Células HL-60 , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/inmunología , Mediciones Luminiscentes , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Imagen Óptica/métodos , Tretinoina/administración & dosificación , Ácido Valproico/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Eur J Haematol ; 94(3): 243-50, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25082346

RESUMEN

We randomised 46 newly diagnosed patients with chronic myeloid leukaemia (median age 56) to receive dasatinib 100 mg QD or imatinib 400 mg QD and report outcome as an intention-to-treat analysis with 36 months follow-up. Early cytogenetic and molecular responses were superior in the dasatinib group, with a tendency that imatinib patients caught up with time. For instance, MR(3.0) was reached at 3 months in 36% vs. 8% (P = 0.02), at 12 months in 81% vs. 46% (P = 0.02) and at 18 months in 73% vs. 65% (n.s.) of the patients in the two groups. In contrast, MR(4.5) was consistently superior in the dasatinib group at all time points from 6 months onwards, reaching 61% vs. 21% (P < 0.05) at 36 months. Sixty-four vs. 71% of the patients in the dasatinib and imatinib arms, respectively, remained on assigned drug. Dasatinib dose was frequently reduced, but with maintained excellent effect. One imatinib patient progressed to blastic phase, but no CML-related deaths occurred. In conclusion, our data compare favourably with those of the dasatinib registration study, DASISION. The fast and deep molecular responses induced by dasatinib compared with imatinib may be exploited to increase the proportion of patients who can achieve a treatment-free remission after treatment discontinuation.


Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Tiazoles/uso terapéutico , Adulto , Anciano , Dasatinib , Esquema de Medicación , Femenino , Estudios de Seguimiento , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Expresión Génica , Humanos , Hidroxiurea/uso terapéutico , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Inducción de Remisión , Riesgo , Análisis de Supervivencia
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