RESUMEN
BACKGROUND: Preclinical studies have shown synergistic antitumour effects between ibrutinib and immune-checkpoint blockade. The aim of this study was to assess the safety and activity of ibrutinib in combination with nivolumab in patients with relapsed or refractory B-cell malignant diseases. METHODS: We did a two-part, open-label, phase 1/2a study at 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the USA. The primary objective of part A (dose escalation) was to assess the safety of daily oral ibrutinib (420 mg or 560 mg) in combination with intravenous nivolumab (3 mg/kg every 2 weeks) to ascertain a recommended phase 2 dose in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, or diffuse large B-cell lymphoma. Dose optimisation was investigated using a modified toxicity probability interval design. The primary objective of the part B expansion phase was to establish the preliminary activity (the proportion of patients who achieved an overall response) of the combination of ibrutinib and nivolumab in four cohorts: relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, diffuse large B-cell lymphoma, and Richter's transformation. All participants who received at least one dose of treatment were included in the primary analysis and analyses were done by disease cohort. This trial is registered with ClinicalTrials.gov, number NCT02329847. The trial is ongoing. FINDINGS: Between March 12, 2015, and April 11, 2017, 144 patients were enrolled in the study. Three patients died before receiving study treatment; thus, 141 patients were included in the analysis, 14 in part A and 127 in part B. One dose-limiting toxicity (grade 3 hyperbilirubinaemia) was reported at the 420 mg dose in the diffuse large B-cell lymphoma cohort, which resolved after 5 days. The combination of ibrutinib and nivolumab led to overall responses in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma, 13 (33%) of 40 patients with follicular lymphoma, 16 (36%) of 45 patients with diffuse large B-cell lymphoma, and 13 (65%) of 20 patients with Richter's transformation. The most common all-grade adverse events were diarrhoea (47 [33%] of 141 patients), neutropenia (44 [31%]), and fatigue (37 [26%]). 11 (8%) of 141 patients had adverse events leading to death; none were reported as drug-related. The most common grade 3-4 adverse events were neutropenia (40 [28%] of 141 patients) and anaemia (32 [23%]). The incidence of grade 3-4 neutropenia ranged from eight (18%) of 45 patients with diffuse large B-cell lymphoma to 19 (53%) of 36 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma; incidence of grade 3-4 anaemia ranged from five (13%) of 40 patients with follicular lymphoma to seven (35%) of 20 patients with Richter's transformation. The most common serious adverse events included anaemia (six [4%] of 141 patients) and pneumonia (five [4%]). The most common grade 3-4 immune-related adverse events were rash (11 [8%] of 141 patients) and increased alanine aminotransferase (three [2%]). INTERPRETATION: The combination of ibrutinib and nivolumab had an acceptable safety profile and preliminary activity was similar to that reported with single-agent ibrutinib in chronic lymphocytic leukaemia or small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. The clinical response in patients with Richter's transformation was promising and supports further clinical assessment. FUNDING: Janssen R&D.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Nivolumab/efectos adversos , Nivolumab/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Seguridad , Adenina/análogos & derivados , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piperidinas , RecurrenciaRESUMEN
Classical Hodgkin lymphoma treatment is evolving rapidly with high response rates from antibody-drug conjugates targeting CD30 and immune checkpoint antibodies. However, most patients do not achieve a complete response, therefore development of novel therapies is warranted to improve patient outcomes. In this phase II study, patients with relapsed or refractory Hodgkin lymphoma were treated with entinostat, an isoform selective histone deacetylase inhibitor. Forty-nine patients were enrolled: 33 patients on Schedule A (10 or 15 mg oral entinostat once every other week); 16 patients on Schedule B (15 mg oral entinostat once weekly in 3 of 4 weeks). Patients received a median of 3 prior treatments (range 1-10), with 80% of the patients receiving a prior stem cell transplant and 8% of patients receiving prior brentuximab vedotin. In the intention-to-treat analysis, the overall response rate was 12% while the disease control rate (complete response, partial response, and stable disease beyond 6 months) was 24%. Seven patients did not complete the first cycle due to progression of disease. Tumor reduction was observed in 24 of 38 (58%) evaluable patients. Median progression-free survival and overall survival was 5.5 and 25.1 months, respectively. The most frequent grade 3 or 4 adverse events were thrombocytopenia (63%), anemia (47%), neutropenia (41%), leukopenia (10%), hypokalemia (8%), and hypophosphatemia (6%). Twenty-five (51%) patients required dose reductions or delays. Pericarditis/pericardial effusion occurred in one patient after 12 cycles of therapy. Future studies are warranted to identify predictive biomarkers for treatment response and to develop mechanism-based combination strategies. (clinicaltrials.gov identifier: 00866333).
Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Piridinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Terapia Combinada , Citocinas/sangre , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/farmacocinética , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Imagen Multimodal , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/farmacocinética , Recurrencia , Retratamiento , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: To evaluate the safety and efficacy of panobinostat plus everolimus in patients with relapsed Hodgkin and non-Hodgkin lymphoma. The concept was supported by the single-agent clinical activity of histone deacetylase inhibitors and mTOR inhibitors, and on the in vitro mechanism-based synergistic antiproliferative activity. EXPERIMENTAL DESIGN: This was a phase I study in patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma using panobinostat orally on Monday/Wednesday/Friday and everolimus orally daily. Toxicity and responses were assessed in dose-escalation cohort followed by expansion cohort at maximum-tolerated dose. Exploratory analysis of serum cytokine levels was performed. RESULTS: Thirty patients were enrolled onto four dose levels. The dose-limiting toxicity was thrombocytopenia. The maximal tolerated dose was panobinostat 20 mg and everolimus 10 mg. Grade 3/4 toxicity included thrombocytopenia (64%), neutropenia (47%), anemia (20%), infection (10%), fatigue (7%), and dyspnea (7%). A total of 10 patients (33%; indolent lymphoma, T-cell lymphoma, mantle cell lymphoma, and Hodgkin lymphoma) achieved objective responses. In patients with Hodgkin lymphoma (n = 14), the overall response rate was 43% with complete response rate of 15%. In patients with Hodgkin lymphoma, multiple serum cytokine levels decreased significantly after treatment with this combination therapy. Of note, clinical responses were associated with a decrease in serum interleukin-5 levels (day 8, P = 0.013, and day 15, P = 0.021). CONCLUSIONS: Our data suggest that the combination therapy is active but with significant thrombocytopenia. Future studies should explore alternate scheduling and different compounds that target the same pathways to improve the tolerability of this novel combination.
Asunto(s)
Enfermedad de Hodgkin/tratamiento farmacológico , Ácidos Hidroxámicos/administración & dosificación , Indoles/administración & dosificación , Linfoma no Hodgkin/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Sirolimus/análogos & derivados , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Esquema de Medicación , Everolimus , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Enfermedad de Hodgkin/sangre , Enfermedad de Hodgkin/patología , Humanos , Interleucina-5/sangre , Linfoma no Hodgkin/sangre , Linfoma no Hodgkin/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Panobinostat , Sirolimus/administración & dosificación , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Overcoming resistance to chemotherapy is the main therapeutic challenge in the treatment of acute lymphocytic leukemia (ALL). Interactions between leukemia cells and the microenvironment promote leukemia cell survival and confer resistance to chemotherapy. Hypoxia is an integral component of bone marrow (BM) microenvironment. Hypoxia-inducible factor-1α (HIF-1), a key regulator of the cellular response to hypoxia, regulates cell growth and metabolic adaptation to hypoxia. HIF-1α expression, analyzed by Reverse Phase Protein Arrays in 92 specimens from newly diagnosed patients with pre-B-ALL, had a negative prognostic impact on survival (p = 0.0025). Inhibition of HIF-1α expression by locked mRNA antagonist (LNA) promoted chemosensitivity under hypoxic conditions, while pharmacological or genetic stabilization of HIF-1α under normoxia inhibited cell growth and reduced apoptosis induction by chemotherapeutic agents. Co-culture of pre-B ALL or REH cells with BM-derived mesenchymal stem cells (MSC) under hypoxia resulted in further induction of HIF-1α protein and acquisition of the glycolytic phenotype, in part via stroma-induced AKT/mTOR signaling. mTOR blockade with everolimus reduced HIF-1α expression, diminished glucose uptake and glycolytic rate and partially restored the chemosensitivity of ALL cells under hypoxia/stroma co-cultures. Hence, mTOR inhibition or blockade of HIF-1α-mediated signaling may play an important role in chemosensitization of ALL cells under hypoxic conditions of the BM microenvironment.
Asunto(s)
Médula Ósea/metabolismo , Médula Ósea/patología , Resistencia a Antineoplásicos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Transducción de Señal , Microambiente Tumoral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Hipoxia de la Célula , Línea Celular Tumoral , Niño , Preescolar , Técnicas de Cocultivo , Resistencia a Antineoplásicos/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Expresión Génica , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Glucólisis/efectos de los fármacos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Lactante , Masculino , Ratones , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Análisis de Supervivencia , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Trasplante Heterólogo , Adulto JovenRESUMEN
TGF-ß-activated kinase 1 (TAK1), a member of the MAPK kinase family, plays a key role in B-cell growth and development. In the present study, we examined the potential role of TAK1 as a therapeutic target for lymphoma. Here, we show that the active phosphorylated form of TAK1 is abundantly expressed in a panel of lymphoma cell lines, including mantle cell, anaplastic large cell, and Hodgkin lymphoma cell lines. Silencing TAK1 expression via the use of siRNA inhibited the activation of NF-κB and p38 and induced apoptosis in lymphoma cell lines. Moreover, submicromolar concentrations of AZ-TAK1, a novel ATP-competitive small molecule inhibitor of TAK1, dephosphorylated TAK1, p38, and IκB-α in lymphoma cell lines. These molecular events were associated with the release of cytochrome c into the cytosol, down-regulation of X-linked inhibitor of apoptosis, activation of caspase 9, and induction of apoptosis. We also demonstrate that primary lymphoma cells express TAK1 and pTAK1 and were sensitive to AZ-TAK1-mediated cell death. Collectively, our data demonstrate an essential role for TAK1 in regulating critical survival mechanisms in lymphoma and suggest that it may serve as a therapeutic target.
Asunto(s)
Linfoma de Células del Manto/enzimología , Quinasas Quinasa Quinasa PAM/fisiología , Apoptosis , Línea Celular Tumoral , Supervivencia Celular/genética , Supervivencia Celular/fisiología , Enfermedad de Hodgkin/enzimología , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Humanos , Proteínas I-kappa B/metabolismo , Linfoma Anaplásico de Células Grandes/enzimología , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patología , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/patología , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Quinasas Quinasa Quinasa PAM/química , Quinasas Quinasa Quinasa PAM/genética , Modelos Moleculares , Inhibidor NF-kappaB alfa , FN-kappa B/metabolismo , Fosforilación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , ARN Interferente Pequeño/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The pan-deacetylase inhibitor panobinostat (LBH589) recently has been shown to have significant clinical activity in patients with relapsed Hodgkin lymphoma, but its mechanism of action in Hodgkin lymphoma remains unknown. In this study, we demonstrate that panobinostat has potent antiproliferative activity against Hodgkin lymphoma-derived cell lines. At the molecular level, panobinostat activated the caspase pathway, inhibited STAT5 and STAT6 phosphorylation, and down-regulated hypoxia-inducible factor 1 α and its downstream targets, glucose transporter 1 (GLUT1) and vascular endothelial growth factor. Paradoxically, panobinostat inhibited LKB1 and AMP-activated protein kinase, leading to activation of mammalian target of rapamycin (mTOR) that promotes survival. Combining panobinostat with the mTOR inhibitor everolimus (RAD001) inhibited panobinostat-induced mTOR activation and enhanced panobinostat antiproliferative effects. Collectively, our data demonstrate that panobinostat is a potent deacetylase inhibitor against Hodgkin lymphoma-derived cell lines, and provide a mechanistic rationale for combining panobinostat with mTOR inhibitors for treating Hodgkin lymphoma patients. Furthermore, the effect of panobinostat on GLUT1 expression suggests that panobinostat may modulate the results of clinical diagnostic imaging tests that depend of functional GLUT1, such as fluorodeoxyglucose positron emission tomography.
Asunto(s)
Apoptosis/efectos de los fármacos , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Ácidos Hidroxámicos/farmacología , Inmunosupresores/farmacología , Sirolimus/análogos & derivados , Quinasas de la Proteína-Quinasa Activada por el AMP , Proteínas Quinasas Activadas por AMP/metabolismo , Western Blotting , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quimiocinas/metabolismo , Citocinas/metabolismo , Sinergismo Farmacológico , Everolimus , Citometría de Flujo , Transportador de Glucosa de Tipo 1/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Enfermedad de Hodgkin/metabolismo , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Indoles , Panobinostat , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Factor de Transcripción STAT5/metabolismo , Factor de Transcripción STAT6/metabolismo , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: The prognosis of patients with relapsed Hodgkin's lymphoma, especially those who relapse after stem-cell transplantation, is poor, and the development of new agents for this patient population is an unmet medical need. We tested the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin's lymphoma. METHODS: Patients with relapsed or refractory classical Hodgkin's lymphoma aged 18 years or older were treated with mocetinostat administered orally three times per week, in 28-day cycles. Two doses were assessed (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary outcome was disease control rate, defined as complete response, partial response, or stable disease (for at least six cycles), analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00358982. FINDINGS: 51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, because toxicity-related dose reductions were necessary in the 110 mg cohort, we treated 28 additional patients with a dose of 85 mg. On the basis of intent-to-treat analysis, the disease control rate was 35% (eight of 23 patients) in the 110 mg group and 25% (seven of 28) in the 85 mg group. 12 patients (24%) discontinued treatment because of adverse events, nine (32%) in the 85 mg cohort and three (13%) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events were neutropenia (four patients [17%] in the 110 mg group, three [11%] in the 85 mg group); fatigue (five patients [22%] in the 110 mg group, three [11%] in the 85 mg group); and pneumonia (four patients [17%] in the 110 mg group, two [7%] in the 85 mg group). Four patients, all in the 110 mg cohort, died during the study, of which two might have been related to treatment. INTERPRETATION: Mocetinostat, 85 mg three times per week, has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin's lymphoma. FUNDING: MethylGene Inc, Montreal, Canada; Celgene Corporation, Summit, NJ, USA; Tufts Medical Center, Boston, MA, USA.
Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Pirimidinas/uso terapéutico , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/patología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , América del Norte , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Recurrencia , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Based on promising in vitro and in vivo activity of several histone deacetylase inhibitors in Hodgkin lymphoma (HL), we investigated SNDX-275, an oral class 1 isoform-selective histone deacetylase inhibitors in HL-derived cell lines. MATERIALS AND METHODS: Proliferation and cell death were examined by MTS assay, Annexin V/propidium iodide, and fluorescence-activated cell sorting analysis. Gene and protein expression were measured by reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemical analysis. A multiplex assay was used to determine cytokines and chemokines. RESULTS: SNDX-275 induced cell death in a dose- and time-dependent manner with an IC(50) at the sub- and lower micromolar range at 72 hours. At the molecular level, SNDX-275 increased histone H3 acetylation, upregulated p21 expression, and activated the intrinsic apoptosis pathway by downregulating the X-linked inhibitor of apoptosis protein. SNDX-275 downregulated expression of antiapoptotic Bcl-2 and Bcl-xL proteins without altering Mcl-1 or Bax levels. Combination studies demonstrated that two Bcl-2 inhibitors (ABT-737 and obatoclax) significantly enhanced the effect of SNDX-275. SNDX-275 modulated the level of several cytokines and chemokines, including interleukin-12 p40-70, interferon-inducible protein-10, RANTES (regulated on activation, normal T expressed and secreted), interleukin-13, interleukin-4, and thymus and activation-regulated chemokine and variably induced the cancer/testis antigen expression of MAGE-A4 and survivin in HL cell lines. CONCLUSIONS: SNDX-275 has antiproliferative activity in HL cell lines, involving several mechanisms: induction of apoptosis, regulation of cytokines and chemokines, and alteration of cancer/testis antigens. Clinical investigation of SNDX-275 alone or in combination with Bcl-2 inhibitors is warranted in patients with HL. Phase 2 studies with SNDX-275 in HL are ongoing, and future clinical studies should investigate combinations with SNDX-275.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/biosíntesis , Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Enfermedad de Hodgkin/patología , Proteínas de Neoplasias/antagonistas & inhibidores , Piridinas/farmacología , Acetilación/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Compuestos de Bifenilo/farmacología , Ácidos Borónicos/farmacología , Bortezomib , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histonas/metabolismo , Humanos , Indoles , Linfoma no Hodgkin/patología , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Nitrofenoles/farmacología , Piperazinas/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Pirazinas/farmacología , Pirroles/farmacología , Sulfonamidas/farmacología , Células Tumorales Cultivadas/efectos de los fármacos , Proteína Inhibidora de la Apoptosis Ligada a X/biosíntesis , Proteína Inhibidora de la Apoptosis Ligada a X/genética , GemcitabinaRESUMEN
In Hodgkin lymphoma (HL), the malignant cells are surrounded by a large number of reactive infiltrating inflammatory cells, including OX40-expressing T cells and interleukin 10 (IL-10)-producing regulatory T (T-reg) cells. These T-reg cells can suppress the immune response and thus contribute to the maintenance of immune tolerance and to insufficient antitumor response. The engagement of OX40L with the OX40 receptor is essential for the generation of antigen-specific memory T cells and for the induction of host antitumor immunity. In the present study, we investigated whether histone deacetylase inhibitors (HDACis) may induce a favorable antitumor immune response by regulating the expression of OX40L in HL. We found that HDACis up-regulated OX40L surface expression in HL cell lines in a dose-dependent manner. Small interfering RNAs (siRNAs) that selectively inhibited HDAC11 expression, significantly up-regulated OX40L and induced apoptosis in HL cell lines, and silencing HDAC11 transcripts increased the production of tumor necrosis-α (TNF-α) and IL-17 in the supernatants of HL cells. Furthermore, HDACI-induced OX40L inhibited the generation of IL-10-producing type 1 T-reg cells. These results demonstrate for the first time that HDAC11 plays an essential role in regulating OX40L expression. Pharmacologic inhibition of HDAC11 may produce a favorable antitumor immune response in patients with HL.
Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Histona Desacetilasas/metabolismo , Enfermedad de Hodgkin/metabolismo , Ligando OX40/biosíntesis , Western Blotting , Línea Celular Tumoral , Separación Celular , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/efectos de los fármacos , Histona Desacetilasas/genética , Enfermedad de Hodgkin/genética , Humanos , Ligando OX40/efectos de los fármacos , Ligando OX40/genética , ARN Interferente Pequeño , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
Although Hodgkin lymphoma (HL) is considered one of the most curable human cancers, the treatment of patients with relapsed and refractory disease, especially those who relapse after autologous stem cell transplantation, remains challenging. Furthermore, because of the young age of these patients, the impact of early mortality on the number of years lost from productive life is remarkable. Patients with relapsed HL post stem cell transplantation currently have no curative therapy, and are in need for new drugs and novel treatment strategies. While no new drugs have been approved for the treatment of patients with HL in more than three decades, several new agents are demonstrating promising results in early clinical trials. This review will focus on the emerging role of histone deacetylase inhibitors in patients with relapsed HL.
Asunto(s)
Inhibidores de Histona Desacetilasas/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/enzimología , Ensayos Clínicos como Asunto , Epigénesis Genética/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Humanos , RecurrenciaRESUMEN
Inhibition of histone deacetylase 6 (HDAC6)-dependent aggresome function by pan HDAC inhibitors was recently reported to be a key mechanism underlying the synergistic activity between proteasome inhibitors and HDAC inhibitors in a variety of tumour types. Because these combinations induce significant thrombocytopenia in vivo, we examined whether less toxic, isotype-selective HDAC inhibitors may still synergize with proteasome inhibitors, and if so, by what mechanisms. Here, we showed that the class I HDAC inhibitor, MGCD0103, has a potent antiproliferative activity in Hodgkin lymphoma (HL) cell lines. Furthermore, MGCD0103 induced tumour necrosis factor α (TNF-α) expression and secretion, which was associated with nuclear factor (NF)-κB activation. Selective inhibition of TNF-α expression by short interfering mRNA, or inhibition of MGCD0103-induced NF-kB activation by proteasome inhibitors enhanced MGCD0103-induced cell death. Thus, our results demonstrate that MGCD0103 may synergize with proteasome inhibitors by HDAC6-independent mechanisms, providing mechanistic rationale for exploring this potentially less toxic combination for the treatment of lymphoma.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Enfermedad de Hodgkin/patología , Pirimidinas/farmacología , Ácidos Borónicos/farmacología , Bortezomib , Citocinas/biosíntesis , Citocinas/genética , Ensayos de Selección de Medicamentos Antitumorales/métodos , Sinergismo Farmacológico , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Desacetilasa 6 , Histona Desacetilasas/fisiología , Humanos , FN-kappa B/metabolismo , Inhibidores de Proteasas/farmacología , Pirazinas/farmacología , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética , Regulación hacia Arriba/efectos de los fármacosRESUMEN
PURPOSE OF REVIEW: Although many advances have been made in the treatment of lymphoma in the past decade, the treatment of patients with relapsed and refractory disease remains challenging. Only a fraction of patients will be cured with salvage therapy and transplantation. For those patients that are either ineligible or relapse after transplant, the treatment options are limited. This illustrates the need for new drugs and novel treatment strategies. This review will focus on the emerging role of histone deacetylase inhibitors (HDACis) in patients with relapsed lymphoma. RECENT FINDINGS: Several HDACis have been evaluated in relapsed and refractory Hodgkin and non-Hodgkin lymphoma showing promising activity in both. Specifically, vorinostat and romidepsin have been approved by the US Food and Drug Administration for patients with relapsed or refractory cutaneous T-cell lymphoma. Several other HDACis have shown very promising activity in Hodgkin lymphoma including panobinostat, entinostat and mocetinostat. SUMMARY: With the limited options available for lymphoma patients in the relapsed and refractory setting, the efficacy demonstrated by HDACis in this patient population is exciting and much needed and will hopefully prompt further investigation into additional agents and into the combination with HDACis.
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Inhibidores de Histona Desacetilasas/uso terapéutico , Linfoma/tratamiento farmacológico , Ensayos Clínicos como Asunto , Humanos , PronósticoRESUMEN
Unselective histone deacetylase (HDAC) inhibitors are a promising novel therapy for lymphoid malignancies. However, these treatments remain empiric as the pattern of HDAC enzymes in different types of cancer, including lymphoid malignancies, remains unknown. We examined the expression of class I and class II HDACs in a panel of cell lines and tissue sections from primary lymphoid tumours. Class I enzymes were highly expressed in all cell lines and primary tumours studied, including the non-malignant reactive cells in the Hodgkin lymphoma (HL) microenvironment. The most frequently altered HDAC expression was HDAC6, as it was either weakly expressed or undetected in 9/14 (64%) of lymphoid cell lines and in 83/89 (93%) of primary lymphoma tissue specimens, including 50/52 (96%) cases of diffuse large B-cell lymphoma, and 18/22 (82%) cases of classical HL. Cell lines that had low expression level of HDAC6 demonstrated aberrant expression of hyper-acetylated tubulin, and were found to be more sensitive to the growth inhibitory effects of the class I HDAC inhibitor MGCD0103. Collectively, our data demonstrate that HDAC6 is rarely expressed in primary lymphoma cases, suggesting that it may not be an important therapeutic target in these lymphoid malignancies.
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Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Enfermedad de Hodgkin/enzimología , Acetilación , Proliferación Celular/efectos de los fármacos , Histona Desacetilasa 6 , Histona Desacetilasas/fisiología , Enfermedad de Hodgkin/patología , Humanos , Isoenzimas/metabolismo , Ganglios Linfáticos/enzimología , Proteínas de Neoplasias/metabolismo , Células de Reed-Sternberg/enzimología , Tubulina (Proteína)/metabolismo , Células Tumorales CultivadasRESUMEN
Epigenetic changes have been implicated in silencing several B-cell genes in Hodgkin and Reed-Sternberg cells (HRS) of Hodgkin lymphoma (HL), and this mechanism has been proposed to promote HRS survival and escape from immunosurveillance. However, the molecular and functional consequences of histone deacetylase (HDAC) inhibition in HL have not been previously described. In this study, we report that the HDAC inhibitor vorinostat induced p21 expression and decreased Bcl-xL levels causing cell-cycle arrest and apoptosis. Furthermore, vorinostat inhibited STAT6 phosphorylation and decreased its mRNA levels in a dose- and time-dependent manner, which was associated with a decrease in the expression and secretion of Thymus and Activation-Regulated Chemokine (TARC/CCL17) and interleukin (IL)-5 and an increase in IP-10 levels. Moreover, vorino-stat inhibited TARC secretion by dendritic cells that were activated by the thymic stromal lymphopoietin (TSLP). Collectively, these data suggest that pharmacologic HDAC inhibition in HL may induce favorable antitumor activity by a direct antiproliferative effect on HRS cells, and possibly by an immune mediated effect by altering cytokine and chemokines secretion in the microenvironment.
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Quimiocina CCL17/biosíntesis , Citocinas/biosíntesis , Enfermedad de Hodgkin/tratamiento farmacológico , Ácidos Hidroxámicos/farmacología , Factor de Transcripción STAT6/antagonistas & inhibidores , Células Th2/efectos de los fármacos , Antineoplásicos/farmacología , Muerte Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Inhibidores de Histona Desacetilasas , Enfermedad de Hodgkin/patología , Humanos , Factor de Transcripción STAT6/metabolismo , Células Th2/metabolismo , VorinostatRESUMEN
OBJECTIVE: To investigate the mechanisms of antiproliferative effect induced by the mammalian target of rapamycin (mTOR) inhibitor temsirolimus in mantle cell lymphoma (MCL). MATERIALS AND METHODS: The antiproliferative effect of temsirolimus on three well-defined MCL cell lines was examined by the MTS assay. Induction of cell-cycle arrest, autophagy, and apoptosis were determined by fluorescence-activated cell sorting analysis. The molecular mechanisms underlining these effects were determined by Western blot. Synergy between temsirolimus and vorinostat were examined by MTS assay and the combination index was calculated. RESULTS: Temsirolimus has antiproliferative activity in three MCL cell lines in a dose- and time-dependent manner. Mechanistically, temsirolimus inhibited mTOR, as evidenced by inhibition of ribosomal S6 phosphorylation, and induced cell-cycle arrest in the G(0)/G(1) phase and a decrease in p21 expression without altering p27 or cyclin D1 levels. Furthermore, temsirolimus increased the number of acidic vesicular organelles and the amount of microtubule-associated protein 1 light-chain 3 processing, which are characteristic of autophagy, without induction of apoptosis. These changes were not associated with alteration in phosphorylated extracellular signal-regulated kinase (ERK), beclin-1, Bax, or Bak levels. In contrast, treatment of these cell lines with the histone deacetylase inhibitor vorinostat decreased ERK phosphorylation, activated caspase 3, and induced apoptosis. Moreover, temsirolimus synergized with submaximal concentrations of vorinostat in all MCL cell lines. CONCLUSION: This is the first report of temsirolimus-induced autophagy in MCL, and of vorinostat inhibition of ERK phosphorylation in MCL. Collectively, these data suggest that the combination of temsirolimus and vorinostat have synergistic antiproliferative activity in MCL cells by distinctively targeting apoptosis and autophagy.
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Autofagia/efectos de los fármacos , Ciclina D1/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Ácidos Hidroxámicos/farmacología , Linfoma de Células del Manto/metabolismo , Sirolimus/análogos & derivados , Antineoplásicos/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Fase G1/efectos de los fármacos , Humanos , Linfoma de Células del Manto/tratamiento farmacológico , Sirolimus/farmacología , VorinostatRESUMEN
The treatment of Hodgkin lymphoma continues to be based on combination chemotherapy and radiation therapy. Although this treatment strategy produces a high cure rate, short- and long-term toxic effects continue to be problematic for young cured patients. In this review we focus on emerging novel therapies using small molecules that target specific survival pathways in the cancer cells. This approach is aimed at improving the cure rate while reducing treatment-related toxicity.