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1.
J Natl Compr Canc Netw ; 18(8): 1125-1134, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32755987

RESUMEN

Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and primary mediastinal B-cell lymphoma are the most common aggressive pediatric mature B-cell non-Hodgkin lymphomas (B-NHLs). Despite excellent survival with current chemotherapy regimens, therapy for Burkitt lymphoma and DLBCL has a high incidence of short- and long-term toxicities. Patients who experience relapse generally have a very poor prognosis. Therefore, novel approaches using targeted therapies to reduce toxicities and improve outcomes in the relapse setting are needed. The addition of rituximab, a monoclonal antibody against CD20, to upfront therapy has improved survival outcomes for high-risk patients and may allow decreased total chemotherapy in those with low-risk disease. Antibody-drug conjugates have been combined with chemotherapy in relapsed/refractory (R/R) NHL, and multiple antibody-drug conjugates are in development. Additionally, bispecific T-cell-engaging antibody constructs and autologous CAR T-cells have been successful in the treatment of R/R acute leukemias and are now being applied to R/R B-NHL with some successes. PD-L1 and PD-L2 on tumor cells can be targeted with checkpoint inhibitors, which restore T-cell-mediated immunity and antitumor responses and can be added to conventional chemotherapy and immune-directed therapies to augment responses. Lastly, trials of small molecule inhibitors targeting cell signaling pathways in NHL subtypes are underway. This article reviews many of the targeted therapies under development that could be considered for future trials in R/R pediatric mature B-NHL.


Asunto(s)
Linfoma de Células B Grandes Difuso , Linfoma no Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Rituximab/uso terapéutico
2.
Br J Haematol ; 185(6): 1111-1124, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30701541

RESUMEN

Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of malignancies. Most NHLs in children, adolescent and young adult patients are aggressive lymphomas that are generally treated with multi-agent chemotherapy or immunochemotherapy regimens. While overall survival is high, the treatment can lead to a high rate of acute and long-term toxicity. However, in the rarer instance of relapsed or refractory disease, outcomes are dismal. Novel therapeutic approaches to the treatment of both T-cell and B-cell NHLs are critical to improve outcomes while also minimising the associated toxicity of current treatment regimes. Potential therapeutic approaches in development include humoral and cellular immunotherapies, small molecule inhibitors of relevant signalling pathways and epigenetic modifying agents. In this review, we will highlight the current state of development of agents of interest with a focus on agents relevant to childhood, adolescent and young adult NHL.


Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Linfoma no Hodgkin/tratamiento farmacológico , Terapia Molecular Dirigida , Adolescente , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Antineoplásicos/farmacología , Niño , Diagnóstico Diferencial , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/etiología , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/etiología , Linfoma no Hodgkin/metabolismo , Terapia Molecular Dirigida/métodos , Clasificación del Tumor , Transducción de Señal/efectos de los fármacos , Adulto Joven
3.
Blood ; 127(9): 1128-37, 2016 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-26675347

RESUMEN

Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and inevitable development of refractory disease, stressing the need to develop alternative therapeutic strategies. To this end, we evaluated pevonedistat (MLN4924), a novel potent and selective NEDD8-activating enzyme inhibitor in a panel of MCL cell lines, primary MCL tumor cells, and 2 distinct murine models of human MCL. Pevonedistat exposure resulted in a dose-, time-, and caspase-dependent cell death in the majority of the MCL cell lines and primary tumor cells tested. Of interest, in the MCL cell lines with lower half-maximal inhibitory concentration (0.1-0.5 µM), pevonedistat induced G1-phase cell cycle arrest, downregulation of Bcl-xL levels, decreased nuclear factor (NF)-κB activity, and apoptosis. In addition, pevonedistat exhibited additive/synergistic effects when combined with cytarabine, bendamustine, or rituximab. In vivo, as a single agent, pevonedistat prolonged the survival of 2 MCL-bearing mouse models when compared with controls. Pevonedistat in combination with rituximab led to improved survival compared with rituximab or pevonedistat monotherapy. Our data suggest that pevonedistat has significant activity in MCL preclinical models, possibly related to effects on NF-κB activity, Bcl-xL downregulation, and G1 cell cycle arrest. Our findings support further investigation of pevonedistat with or without rituximab in the treatment of MCL.


Asunto(s)
Ciclopentanos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Pirimidinas/uso terapéutico , Rituximab/uso terapéutico , Ubiquitinas/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Separación Celular , Supervivencia Celular/efectos de los fármacos , Ciclopentanos/farmacología , Inhibidores Enzimáticos/farmacología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/patología , Ratones SCID , Proteína NEDD8 , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Pirimidinas/farmacología , Rituximab/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Ubiquitinas/metabolismo
4.
Br J Haematol ; 179(5): 739-747, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-29082519

RESUMEN

Treatment with dose-adjusted EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy and rituximab (DA-EPOCH-R) has become the standard of care for primary mediastinal B-cell lymphoma (PMBCL) at many institutions despite limited data in the multi-centre setting. We report a large, multi-centre retrospective analysis of children and adults with PMBCL treated with DA-EPOCH-R to characterize outcomes and evaluate prognostic factors. We assessed 156 patients with PMBCL treated with DA-EPOCH-R across 24 academic centres, including 38 children and 118 adults. All patients received at least one cycle of DA-EPOCH-R. Radiation therapy was administered in 14·9% of patients. With median follow-up of 22·6 months, the estimated 3-year event-free survival (EFS) was 85·9% [95% confidence interval (CI) 80·3-91·5] and overall survival was 95·4% (95% CI 91·8-99·0). Outcomes were not statistically different between paediatric and adult patients. Thrombotic complications were reported in 28·2% of patients and were more common in paediatric patients (45·9% vs. 22·9%, P = 0·011). Seventy-five per cent of patients had a negative fluorodeoxyglucose positron emission tomography (FDG-PET) scan at the completion of DA-EPOCH-R, defined as Deauville score 1-3. Negative FDG-PET at end-of-therapy was associated with improved EFS (95·4% vs. 54·9%, P < 0·001). Our data support the use of DA-EPOCH-R for the treatment of PMBCL in children and adults. Patients with a positive end-of-therapy FDG-PET scan have an inferior outcome.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Neoplasias del Mediastino/tratamiento farmacológico , Adolescente , Adulto , Factores de Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Esquema de Medicación , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/radioterapia , Masculino , Neoplasias del Mediastino/diagnóstico por imagen , Neoplasias del Mediastino/patología , Neoplasias del Mediastino/radioterapia , Persona de Mediana Edad , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Prednisona/administración & dosificación , Prednisona/efectos adversos , Pronóstico , Radioterapia Adyuvante , Estudios Retrospectivos , Rituximab/administración & dosificación , Rituximab/efectos adversos , Trombosis/inducido químicamente , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversos , Adulto Joven
5.
Br J Haematol ; 173(4): 597-616, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-27062282

RESUMEN

With the introduction of the anti-CD20 monoclonal antibody rituximab, B-cell non-Hodgkin lymphoma was the first malignancy successfully treated with an immunotherapeutic agent. Since then, numerous advances have expanded the repertoire of immunotherapeutic agents available for the treatment of a variety of malignancies, including many lymphoma subtypes. These include the introduction of monoclonal antibodies targeting a variety of cell surface proteins, including the successful targeting of immunoregulatory checkpoint receptors present on T-cells or tumour cells. Additionally, cellular immunotherapeutic approaches utilize T- or Natural Killer-cells generated with chimeric antigen receptors against cell surface proteins or Epstein-Barr virus-associated latent membrane proteins. The following review describes the current state of immunotherapy for non-Hodgkin lymphoma including a summary of currently available data and promising agents currently in clinical development with future promise in the treatment of childhood, adolescent and young adult non-Hodgkin lymphoma.


Asunto(s)
Inmunoterapia/métodos , Linfoma no Hodgkin/tratamiento farmacológico , Adolescente , Anticuerpos Monoclonales/uso terapéutico , Ingeniería Celular , Niño , Preescolar , Humanos , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/patología , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/inmunología , Terapia Molecular Dirigida/métodos , Adulto Joven
6.
Br J Haematol ; 171(5): 763-75, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26471982

RESUMEN

Obinutuzumab is a novel glycoengineered Type-II CD20 monoclonal antibody. CD20 is expressed in approximately 100% of children and adolescents with Burkitt lymphoma (BL) and 40% with precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL). We evaluated the anti-tumour activity of obinutuzumab versus rituximab against rituximab-resistant (Raji 4RH) and -sensitive (Raji) BL and pre-B-ALL (U698-M) cells in vitro and in human BL or Pre-B-ALL xenografted mice. We demonstrated that obinutuzumab compared to rituximab significantly enhanced cell death against Raji 35·6 ± 3·1% vs. 25·1 ± 2·0%, (P = 0·001), Raji4RH 19·7 ± 2·2% vs. 7·9 ± 1·5% (P = 0·001) and U-698-M 47·3 ± 4·9% vs. 23·2 ± 0·5% (P = 0·001), respectively. Obinutuzumab versus rituximab also induced a significant increase in antibody-dependent cellular cytotoxicity (ADCC) with K562-IL15-41BBL expanded NK cells against Raji 73·8 ± 8·1% vs. 56·81 ± 4·6% (P = 0·001), Raji-4RH 40·0 ± 1·6% vs. 0·5 ± 1·1% (P = 0·001) and U-698-M 70·0 ± 1·6% vs. 45·5 ± 0·1% (P = 0·001), respectively. Overall survival in tumour xenografted mice receiving 30 mg/kg of obinutuzumab was significantly increased when compared to those receiving 30 mg/kg of rituximab in BL; Raji (P = 0·05), Raji4RH (P = 0·02) and U698-M (P = 0·03), respectively. These preclinical data suggest obinutuzumab is significantly superior to rituximab in inducing cell death, ADCC and against rituximab-sensitive/-resistant BL and pre-B-ALL xenografted mice. Taken together, these preclinical results provide evidence to suggest that future investigation of obinutuzumab is warranted in patients with relapsed/refractory CD20(+) BL and/or pre-B-ALL.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos/farmacología , Linfoma de Burkitt/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Rituximab/farmacología , Animales , Apoptosis/efectos de los fármacos , Caspasas/efectos de los fármacos , Caspasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Interferón gamma/biosíntesis , Células Asesinas Naturales/efectos de los fármacos , Proteína 1 de la Membrana Asociada a los Lisosomas/metabolismo , Ratones , Terapia Molecular Dirigida/métodos , Trasplante de Neoplasias , Análisis de Supervivencia , Trasplante Heterólogo
7.
Br J Haematol ; 169(4): 506-19, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25712263

RESUMEN

Histone deacetylases (HDACs) inhibitors are active in T-cell lymphoma and are undergoing pre-clinical and clinical testing in other neoplasms. Entinostat is an orally bioavailable class I HDAC inhibitor with a long half-life, which is under evaluation in haematological and solid tumour malignancies. To define the activity and biological effects of entinostat in B-cell lymphoma we studied its anti-tumour activity in several rituximab-sensitive or -resistant pre-clinical models. We demonstrated that entinostat is active in rituximab-sensitive cell lines (RSCL), rituximab-resistant cell lines (RRCL) and primary tumour cells isolated from lymphoma patients (n = 36). Entinostat exposure decreased Bcl-XL (BCL2L1) levels and induced apoptosis in cells. In RSCL and RRCL, entinostat induced p21 (CDKN1A) expression leading to G1 cell cycle arrest and exhibited additive effects when combined with bortezomib or cytarabine. Caspase inhibition diminished entinostat activity in some primary tumour cells suggesting that entinostat has dual mechanisms-of-action. In addition, entinostat increased the expression of CD20 and adhesion molecules. Perhaps related to these effects, we observed a synergistic activity between entinostat and rituximab in a lymphoma-bearing severe combined immunodeficiency (SCID) mouse model. Our data suggests that entinostat is an active HDAC inhibitor that potentiates rituximab activity in vivo and supports its further clinical development in B-cell lymphoma.


Asunto(s)
Anticuerpos Monoclonales de Origen Murino/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzamidas/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Linfoma de Células B/tratamiento farmacológico , Piridinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Ácidos Borónicos/farmacología , Bortezomib , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Citarabina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Masculino , Ratones , Ratones SCID , Pirazinas/farmacología , Rituximab , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína bcl-X/metabolismo
8.
Br J Haematol ; 170(3): 367-71, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25858645

RESUMEN

Patient-specific primers from 10 children/adolescents with Burkitt leukaemia (BL) ± central nervous system disease who were treated with French-British-American/Lymphome Malins de Burkitt 96 C1 plus rituximab were developed from diagnostic blood/bone marrow. Minimal residual disease (MRD) was assessed by real-time polymerase chain reaction at the end of induction (EOI) and consolidation (EOC). Seventy per cent (7/10) and 71% (5/7) were MRD-positive at EOI and EOC, respectively, with no disease recurrences. MRD after induction and consolidation did not predict relapse and subsequent therapy appeared to eliminate MRD. Thus, assessing MRD at a later time point is warranted in future trials to determine its clinical significance.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Burkitt/sangre , Linfoma de Burkitt/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/sangre , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Quimioterapia de Consolidación , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Neoplasia Residual , Proyectos Piloto , Reacción en Cadena en Tiempo Real de la Polimerasa
9.
Br J Haematol ; 162(5): 678-83, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23802659

RESUMEN

The ANHL01P1 trial was undertaken to determine pharmacokinetics and safety following the addition of rituximab to French-American-British/Lymphome Malins de Burkitt (FAB/LMB96) chemotherapy in 41 children and adolescents with Stage III/IV mature B-cell lymphoma/leukaemia. Patients received rituximab (375 mg/m(2) ) days -2 and 0 of two induction cycles and day 0 of two consolidation cycles. Highest peak levels were achieved following the second dose of each induction cycle [299 ± 19 and 384 ± 25 µg/ml (Group-B); 245 ± 31 and 321 ± 32 µg/ml (Group-C)] with sustained troughs and t½ of 26-29 d. Rituximab can be safely added to FAB chemotherapy with high early rituximab peak/trough levels and a long t½.


Asunto(s)
Anticuerpos Monoclonales de Origen Murino/sangre , Antineoplásicos/sangre , Linfoma de Células B/sangre , Adolescente , Adulto , Factores de Edad , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Esquema de Medicación , Semivida , Humanos , L-Lactato Deshidrogenasa/sangre , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/patología , Metotrexato/uso terapéutico , Estadificación de Neoplasias , Proyectos Piloto , Prednisona/uso terapéutico , Rituximab , Vincristina/uso terapéutico , Adulto Joven
10.
Future Oncol ; 9(12): 1829-39, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24295413

RESUMEN

Ofatumumab is a fully human, IgG anti-CD20 monoclonal antibody codeveloped by GlaxoSmithKline (Brentford, UK) and Genmab (Copenhagen, Denmark). In preclinical studies, ofatumumab exhibited more potent in vitro activity than rituximab against B-cell malignancies and prolonged survival in in vivo animal models compared with rituximab. Ofatumumab is clinically well tolerated with initial infusion reactions being the predominant associated toxicity. Ofatumumab has demonstrated efficacy in relapsed/refractory chronic lymphocytic leukemia (CLL) and has received regulatory approval in both Europe and the USA for treatment of fludarabine and alemtuzumab refractory disease. Single-agent ofatumumab has resulted in overall response rates of 42-51% in relapsed/refractory CLL and up to 80% when combined with chemotherapy. In de novo CLL, overall response rates of 77-78% have been achieved.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Alemtuzumab , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Antígenos CD20/inmunología , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Ratones , Recurrencia Local de Neoplasia/patología , Rituximab , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados
11.
Blood Cancer Discov ; 4(3): 208-227, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-36723991

RESUMEN

The rarity of malignant Hodgkin and Reed Sternberg (HRS) cells in classic Hodgkin lymphoma (cHL) limits the ability to study the genomics of cHL. To circumvent this, our group has previously optimized fluorescence-activated cell sorting to purify HRS cells. Using this approach, we now report the whole-genome sequencing landscape of HRS cells and reconstruct the chronology and likely etiology of pathogenic events leading to cHL. We identified alterations in driver genes not previously described in cHL, APOBEC mutational activity, and the presence of complex structural variants including chromothripsis. We found that high ploidy in cHL is often acquired through multiple, independent chromosomal gains events including whole-genome duplication. Evolutionary timing analyses revealed that structural variants enriched for RAG motifs, driver mutations in B2M, BCL7A, GNA13, and PTPN1, and the onset of AID-driven mutagenesis usually preceded large chromosomal gains. This study provides a temporal reconstruction of cHL pathogenesis. SIGNIFICANCE: Previous studies in cHL were limited to coding sequences and therefore not able to comprehensively decipher the tumor complexity. Here, leveraging cHL whole-genome characterization, we identify driver events and reconstruct the tumor evolution, finding that structural variants, driver mutations, and AID mutagenesis precede chromosomal gains. This article is highlighted in the In This Issue feature, p. 171.


Asunto(s)
Enfermedad de Hodgkin , Células de Reed-Sternberg , Humanos , Células de Reed-Sternberg/patología , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Citometría de Flujo , Evolución Molecular
12.
Br J Haematol ; 156(4): 490-8, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22150234

RESUMEN

Ofatumumab is a new monoclonal antibody (mAb) targeting a novel membrane-proximal epitope on CD20. To better define ofatumumab's activity, we conducted pre-clinical studies in rituximab-sensitive cell lines (RSCL), rituximab-resistant cell lines (RRCL), ofatumumab-exposed cell lines (OECLs), primary lymphoma cells, and a lymphoma xenograft model. RRCL and OECL were generated by repeated exposure of sensitive cells to escalating doses of rituximab or ofatumumab ± human serum. Antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CMC) assays were performed to assess cellular sensitivity to rituximab or ofatumumab. Ofatumumab elicited a higher rate of CMC in RSCL, RRCL and primary tumour cells. The chronic exposure of lymphoma cells to ofatumumab resulted in rituximab resistance but less ofatumumab resistance. In an in vivo severe combined immunodeficiency mouse model of human lymphoma, ofatumumab prolonged median survival compared to rituximab. While rituximab CMC diminished with CD20 down-regulation in RRCL passages, ofatumumab activity in vitro diminished to a lesser degree. Our data suggest that ofatumumab is more potent than rituximab in rituximab-sensitive or rituximab-resistant models and has the potential to decrease the development of biological resistance in patients with repeated exposure to anti-CD20 mAbs.


Asunto(s)
Anticuerpos Monoclonales de Origen Murino/farmacología , Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Linfoma de Células B/metabolismo , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Antígenos CD20/genética , Antígenos CD20/metabolismo , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Proteínas del Sistema Complemento/metabolismo , Citotoxicidad Inmunológica/efectos de los fármacos , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/genética , Ratones , Ratones SCID , Rituximab , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Accid Anal Prev ; 155: 106095, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33798797

RESUMEN

This research is aimed at investigating drivers' attitudes towards connected vehicle technology in general and two connected vehicle applications in particular-Lane Speed Monitoring and High Speed Differential Warning-which have been demonstrated via simulation to be effective in enhancing traffic mobility and safety, respectively. An online survey was sent to customers of an automobile manufacturer in the United States. Out of the 1453 survey responses that were received, 650 complete and valid responses were used to analyze the respondents' stated acceptance of and expected behavioral responses to the two connected vehicle applications under a variety of scenarios. Statistical analyses were conducted to examine the influence of demographic and socioeconomic factors. The results reveal that the respondents express high willingness to use connected vehicle technology and the two applications under various circumstances, and the willingness is strongly associated with age, gender, education level, and income. Higher levels of acceptance are observed in older, male, higher-educated, or higher-income respondents, while the patterns of conditional acceptance and expected behavioral responses vary with specific scenarios. These results provide useful information for application developers, traffic operators, and policy makers to steer connected vehicle technology development and deployment in the direction that will benefit both the users and the society.


Asunto(s)
Conducción de Automóvil , Accidentes de Tránsito/prevención & control , Anciano , Automóviles , Simulación por Computador , Humanos , Masculino , Tecnología
14.
Cancer Discov ; 11(6): 1424-1439, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33563661

RESUMEN

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. SIGNIFICANCE: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations.See related commentary by Bornhauser and Bourquin, p. 1322.This article is highlighted in the In This Issue feature, p. 1307.


Asunto(s)
Leucemia/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Biomarcadores de Tumor/genética , Niño , Estudios de Cohortes , Progresión de la Enfermedad , Estudios de Factibilidad , Femenino , Humanos , Leucemia/genética , Leucemia/mortalidad , Masculino , Terapia Molecular Dirigida , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Estudios Prospectivos , Estados Unidos
15.
Blood Adv ; 2(23): 3516-3525, 2018 12 11.
Artículo en Inglés | MEDLINE | ID: mdl-30530779

RESUMEN

Clinical observations suggest the existence of shared resistance pathways between rituximab and chemotherapy agents. To explore the mechanisms of rituximab resistance, our group created rituximab-resistant cell lines (RRCLs), which display altered expression of several inhibitor of apoptosis (IAP) family proteins. Here, we provide evidence to support pharmacologically targeting IAPs in lymphoma with LCL-161, a small molecule mimetic of the second mitochondria-derived activator of caspases (SMAC). The antitumor effect of LCL-161 was determined using luminescent adenosine triphosphate assays, flow cytometry, SCID mouse xenografts, and ex vivo patient biopsy sample studies. In vitro exposure to LCL-161 also resulted in a dose-dependent decrease in IAP levels, along with synergistic enhancement of the antitumor effect of cytotoxic chemotherapy, in rituximab-sensitive cell lines and RRCLs. In addition, LCL-161 increased the cytotoxic effect of the proteasome inhibitor carfilzomib in ex vivo lymphoma patient samples. The combination of LCL-161 with the chemotherapy regimen rituximab, gemcitabine, and vinorelbine (RGV) improved in vivo survival compared with RGV alone in severe combined immunodeficient mice implanted with RRCLs but not in animals implanted with rituximab-sensitive cell lines. In summary, LCL-161 exhibits synergistic antitumor activity in both in vitro and in vivo models of resistant lymphoma. Our data support further preclinical investigation of LCL-161 as a novel antilymphoma agent.


Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Oligopéptidos/química , Tiazoles/farmacología , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Quimioterapia Combinada , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/patología , Ratones , Ratones SCID , Oligopéptidos/farmacología , Oligopéptidos/uso terapéutico , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Rituximab/farmacología , Rituximab/uso terapéutico , Survivin/genética , Survivin/metabolismo , Tiazoles/uso terapéutico , Trasplante Heterólogo
16.
Oncotarget ; 9(31): 21820-21830, 2018 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-29774105

RESUMEN

Though outcomes for pediatric Burkitt lymphoma (BL) have improved significantly in recent decades with intensive multi-agent chemotherapy and the addition of rituximab, chemotherapy resistance remains a significant impediment to cure following relapse. Activation of the PI3K/AKT pathway has been implicated in Burkitt lymphomagenesis and increased PI3K/AKT activation has been associated with worse outcomes in adults with aggressive B-cell non-Hodgkin lymphoma (B-NHL). Inhibitors of the PI3K/AKT pathway have been approved for the treatment of refractory indolent B-NHL and continue to be investigated for treatment of aggressive B-NHLs. We investigated the activation of the PI3K/AKT pathway in a cell line model of resistant BL and the ability to target this pathway with small molecule inhibitors in BL cell lines. We found that cell lines resistant to rituximab and chemotherapy exhibited increased activation of PI3K/AKT and that inhibition of AKT or PI3K results in in vitro anti-lymphoma activity. To investigate the role of PI3K/AKT activation on the efficacy of cytotoxic chemotherapy, we exposed cells to inhibitors in combination with chemotherapy and noted a synergistic increase in response to chemotherapy. Overall these findings highlight the role of PI3K/AKT in chemotherapy resistance in BL cells and may represent a tractable therapeutic target.

17.
Leuk Lymphoma ; 58(4): 766-772, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27643446

RESUMEN

Pegaspargase is a mainstay in the treatment of acute lymphoblastic leukemia. When intravenous (IV) infusion replaced intramuscular (IM) injection as the standard route of administration, there were early reports suggested an increased hypersensitivity reactions (HSRs) rate with IV administration. There have since been eight published reports comparing the incidence of HSRs occurring with IV versus IM pegaspargase. This review analyzes the reports and summarizes their consistent findings where feasible. For grade 3-4 HSRs, the rates are comparable with IV and IM administration. Grade 2 HSRs appear to be more likely with IV than IM administration but the validity of the difference is uncertain. Multiple factors confound the analyses, including the historically controlled nature of the comparisons and the increased likelihood of reporting adverse reactions with IV administration. In summary, the reports do not support the conclusion that pegaspargase-induced HSR rate is more frequent with IV administration.


Asunto(s)
Antineoplásicos/efectos adversos , Asparaginasa/efectos adversos , Hipersensibilidad a las Drogas/inmunología , Polietilenglicoles/efectos adversos , Factores de Edad , Antineoplásicos/administración & dosificación , Asparaginasa/administración & dosificación , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/epidemiología , Humanos , Incidencia , Infusiones Intravenosas , Inyecciones Intramusculares , Polietilenglicoles/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Índice de Severidad de la Enfermedad
18.
Oncotarget ; 8(69): 113895-113909, 2017 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-29371955

RESUMEN

We recently demonstrated that obinutuzumab (GA101), a novel glycoengineered type II CD20 Ab compared to rituximab (RTX) mediates significantly enhanced antibody-dependent cell cytotoxicity (ADCC) in vitro and increased overall survival in a Burkitt lymphoma (BL) xenograft non-obese diabetic severe combined immunodeficiency gamma (NSG) model. In this study we compared the phosphoproteomic changes by pathway analysis following obinutuzumab vs RTX against RTX-sensitive (Raji) and -resistant BL (Raji4RH). Phosphoproteomic analyses were performed by mass-spectrometry (MS)-based label-free quantitative phosphoproteomic profiling. We demonstrated that 418 proteins in Raji and 377 proteins in Raji 4RH, were differentially phosphorylated (>1.5-fold) after obinutuzumab vs. RTX. Proteins that were significantly differentially phosphorylated included the B cell antigen receptor (BCR) (PLCG2, BTK and GSK3B), Fc gamma phagocytosis (FCRG2B, MAPK1, PLCG2 and RAF1), and natural killer cell-mediated cytotoxicity (MAPK1, RAF1, PLCG2 and MAPK3) signaling pathways. Differential phosphorylation of BCR or cytotoxicity pathway proteins revealed significant up-regulation of BTK, PLCY2 and ERK1/RAF1 after obinutuzumab compared to RTX. Silencing of PLCG2 in the BCR and MAPK1 in the cytotoxicity pathway significantly increased BL proliferation and decreased BL cytotoxicity after obinutuzumab compared to RTX. These results in combination with our previous results demonstrating a significant improvement in in vitro BL cytotoxicity and in vivo BL survival by obinutuzumab compared to RTX may in part be due to differential effects on selected BL protein signaling pathways.

19.
Mol Cancer Ther ; 16(9): 1779-1790, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28619753

RESUMEN

Hsp90 is a molecular chaperone that protects proteins, including oncogenic signaling complexes, from proteolytic degradation. PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets the functionally distinct pool of Hsp90 present in tumor cells. Tumors that are driven by the MYC oncoprotein may be particularly sensitive to PU-H71 due to the essential role of Hsp90 in the epichaperome, which maintains the malignant phenotype in the setting of MYC. Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by MYC dysregulation. In this study, we evaluated Hsp90 as a potential therapeutic target in BL. We found that primary BL tumors overexpress Hsp90 and that Hsp90 inhibition has antitumor activity in vitro and in vivo, including potent activity in a patient-derived xenograft model of BL. To evaluate the targets of PU-H71 in BL, we performed high-affinity capture followed by proteomic analysis using mass spectrometry. We found that Hsp90 inhibition targets multiple components of PI3K/AKT/mTOR signaling, highlighting the importance of this pathway in BL. Finally, we found that the anti-lymphoma activity of PU-H71 is synergistic with dual PI3K/mTOR inhibition in vitro and in vivo Overall, this work provides support for Hsp90 as a therapeutic target in BL and suggests the potential for combination therapy with PU-H71 and inhibitors of PI3K/mTOR. Mol Cancer Ther; 16(9); 1779-90. ©2017 AACR.


Asunto(s)
Antineoplásicos/farmacología , Linfoma de Burkitt/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Animales , Apoptosis/efectos de los fármacos , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/genética , Linfoma de Burkitt/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Expresión Génica , Proteínas HSP90 de Choque Térmico/genética , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Masculino , Ratones , Proteómica/métodos , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética
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