RESUMEN
Histone deacetylase (HDAC) inhibitors are emerging as promising treatments for hematological malignancies, with potential applications extending to solid tumors in the future. Given their wide-ranging biological effects, there is a pressing need for a thorough understanding of the toxicities linked to HDAC inhibition. In this study, a pharmacovigilance analysis was conducted using the FDA Adverse Event Reporting System database. Suspected adverse events linked to HDAC inhibitors were detected through various statistical methodologies, including reporting odds ratio, proportional reporting ratio, information component, and Empirical Bayes Geometric Mean. Our study findings have illuminated that, among the total reported cases examined, gastrointestinal disorders accounted for 13% patients of the cohort, while lymphatic system disorders comprised 8% cases of the cohort, all of which manifested as adverse events induced by HDAC inhibitors. Importantly, the usage of HDAC inhibitors was found to be associated with incidents of atrial fibrillation, heart failure, respiratory failure, hepatic dysfunction, and acute kidney injury. Romidepsin and belinostat demonstrated more pronounced signals of adverse events compared to panobinostat and vorinostat, emphasizing the need for vigilant monitoring of adverse events in this particular population. Furthermore, atrial fibrillation (clinical priority score of 7 points) emerged as the paramount medical event warranting utmost clinical attention. Eventually, multiple adverse events were observe to emerge within the initial and second months following the initiation of treatment. Vigilant monitoring and supportive care strategies are critical in addressing the toxicities associated with HDAC inhibitors, particularly those concerning cardiotoxicity, respiratory toxicity, renal toxicity, and hepatotoxicity.
Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Inhibidores de Histona Desacetilasas , Farmacovigilancia , Humanos , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Vorinostat/efectos adversos , Panobinostat/efectos adversos , Ácidos Hidroxámicos/efectos adversos , Ácidos Hidroxámicos/uso terapéutico , Depsipéptidos/efectos adversos , Estados Unidos/epidemiología , Enfermedades Gastrointestinales/inducido químicamente , Teorema de Bayes , Neoplasias Hematológicas/tratamiento farmacológico , Fibrilación Atrial/inducido químicamente , Fibrilación Atrial/tratamiento farmacológico , Adolescente , Adulto Joven , Anciano de 80 o más Años , SulfonamidasRESUMEN
Panobinostat is an oral pan histone-deacetylase inhibitor used in the treatment of relapsed and refractory multiple myeloma. Previously published studies of panobinostat demonstrated synergy with bortezomib but included few patients exposed to newer agent combinations (ie, panobinostat plus daratumumab or carfilzomib). Here, we report outcomes of panobinostat-based combinations at an academic medical center among patients whose disease had been heavily pretreated with modern agents. We retrospectively analyzed 105 patients with myeloma treated with panobinostat at The Mount Sinai Hospital in New York City between October 2012 and October 2021. These patients had a median age of 65 (range 37-87) and had received a median of 6 prior lines of therapy while in 53% the disease was classified as triple class refractory and in 54% the disease had high-risk cytogenetics. Panobinostat was most commonly utilized at 20 mg (64.8%) as part of a triplet (61.0%) or quadruplet (30.5%). Aside from steroids, panobinostat was most commonly administered in combination with lenalidomide, pomalidomide, carfilzomib, and daratumumab in descending order of frequency. Among the 101 response-evaluable patients, the overall response rate was 24.8%, clinical benefit rate (≥minimal response) was 36.6%, and median progression-free survival was 3.4 months. Median overall survival was 19.1 months. The most common toxicities ≥grade 3 were hematologic, primarily neutropenia (34.3%), thrombocytopenia (27.6%), and anemia (19.1%). Panobinostat-based combinations produced modest response rates in patients with heavily pretreated multiple myeloma, over half of whom had triple-class refractory disease. Panobinostat warrants continued investigation as a tolerable oral option for recapturing responses in patients whose disease has progressed after receipt of standard-of-care therapies.
Asunto(s)
Mieloma Múltiple , Humanos , Panobinostat/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Estudios Retrospectivos , Indoles/efectos adversos , Ácidos Hidroxámicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , DexametasonaRESUMEN
PURPOSE: Belinostat is an intravenous histone deacetylase inhibitor with approval for T-cell lymphomas. Adavosertib is a first in class oral Wee1 inhibitor. Preclinical studies of the combination demonstrated synergy in various human acute myeloid leukemia (AML) lines as well as AML xenograft mouse models. EXPERIMENTAL DESIGN: This was a phase 1 dose-escalation study of belinostat and adavosertib in patients with relapsed/refractory AML and myelodysplastic syndrome (MDS). Patients received both drugs on days 1-5 and 8-12 of a 21-day cycle. Safety and toxicity were monitored throughout the study. Plasma levels of both drugs were measured for pharmacokinetic analysis. Response was determined by standard criteria including bone marrow biopsy. RESULTS: Twenty patients were enrolled and treated at 4 dose levels. A grade 4 cytokine release syndrome at dose level 4 (adavosertib 225 mg/day; belinostat 1000 mg/m2) qualified as a dose-limiting toxicity event. The most common non-hematologic treatment-related adverse events were nausea, vomiting, diarrhea, dysgeusia, and fatigue. No responses were seen. The study was terminated prior to maximum tolerated dose/recommended phase 2 dose determination. CONCLUSIONS: The combination of belinostat and adavosertib at the tested dose levels was feasible but without efficacy signals in the relapsed/refractory MDS/AML population.
Asunto(s)
Ácidos Hidroxámicos , Leucemia Mieloide Aguda , Humanos , Animales , Ratones , Ácidos Hidroxámicos/efectos adversos , Pirimidinonas/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patologíaRESUMEN
Cancer cachexia is mainly characterized by wasting of skeletal muscles and fat and body weight loss, along with severe complications of major organs like liver, heart, brain and bone. There can be diminishing performance of these major organs as cancer cachexia progresses, one such drastic effect on the cardiac system. In the present study, differential effect of histone deacetylase inhibitors (HDACi) on cardiac complications associated with cancer cachexia is studied. Two models were used to induce cancer cachexia: B16F1 induced metastatic cancer cachexia and Lewis lung carcinoma cell - induced cancer cachexia. Potential of Class I HDACi entinostat, Class II HDACi MC1568, and nonspecific HDACi sodium butyrate on cardiac complications were evaluated using the cardiac hypertrophy markers, hemodynamic markers, and cardiac markers along with histopathological evaluation of heart sections by Periodic acid-Schiff staining, Masson's trichrome staining, Picro-sirius red staining, and haematoxylin and eosin staining. Immunohistochemistry evaluation by vimentin and caspase 3 protein expression was evaluated. Entinostat showed promising results by attenuating the cardiac complications, and MC1568 treatment further exacerbated the cardiac complications, while non-conclusive effect were recorded after treatment with sodium butyrate. This study will be helpful in evaluating other HDACi for potential in cardiac complications associated with cancer cachexia.
Asunto(s)
Benzamidas/uso terapéutico , Caquexia/tratamiento farmacológico , Caquexia/etiología , Cardiopatías/tratamiento farmacológico , Cardiopatías/etiología , Inhibidores de Histona Desacetilasas/uso terapéutico , Neoplasias/complicaciones , Piridinas/uso terapéutico , Animales , Benzamidas/farmacología , Ácido Butírico , Línea Celular Tumoral , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/efectos adversos , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Piridinas/farmacología , Pirroles/efectos adversosRESUMEN
Older patients with acute myeloid leukaemia (AML) account for nearly half of those with the disease. Because they are perceived to be unfit for, unwilling to receive, or unlikely to benefit from conventional chemotherapy they represent an important unmet need. Tosedostat is a selective oral aminopeptidase inhibitor, which in phase I/II trials showed acceptable toxicity and encouraging efficacy. We report the only randomised study of low-dose cytosine arabinoside (LDAC) combined with tosedostat (LDAC-T) versus LDAC in untreated older patients not suitable for intensive treatment. A total of 243 patients were randomised 1:1 as part of the 'Pick-a-Winner' LI-1 trial. There was a statistically non-significant increase in the complete remission (CR) rate with the addition of tosedostat, LDAC-T 19% versus LDAC 12% [odds ratio (OR) 0·61, 95% confidence interval (CI) 0·30-1·23; P = 0·17]. For overall response (CR+CR with incomplete recovery of counts), there was little evidence of a benefit to the addition of tosedostat (25% vs. 18%; OR 0·68, 95% CI 0·37-1·27; P = 0·22). However, overall survival (OS) showed no difference (2-year OS 16% vs. 12%, hazard ratio 0·97, 95% CI 0·73-1·28; P = 0·8). Exploratory analyses failed to identify any subgroup benefitting from tosedostat. Despite promising pre-clinical, early non-randomised clinical data with acceptable toxicity and an improvement in response, we did not find evidence that the addition of tosedostat to LDAC produced a survival benefit in this group of patients with AML. International Standard Randomised Controlled Trial Number: ISRCTN40571019.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Citarabina/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Glicina/análogos & derivados , Ácidos Hidroxámicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Factores de Edad , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citarabina/administración & dosificación , Citarabina/efectos adversos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Femenino , Glicina/administración & dosificación , Glicina/efectos adversos , Glicina/uso terapéutico , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/efectos adversos , Leucemia Mieloide Aguda/epidemiología , Masculino , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
PURPOSE: Effective second-line chemotherapy options are limited in treating advanced biliary tract cancers (BTCs). Resminostat is an oral histone deacetylase inhibitor. Such inhibitors increase sensitivity to fluorouracil, the active form of S-1. In the phase I study, addition of resminostat to S-1 was suggested to have promising efficacy for pre-treated BTCs. This study investigated the efficacy and safety of resminostat plus S-1 in second-line therapy for BTCs. METHODS: Patients were randomly assigned to receive resminostat or placebo (200 mg orally per day; days 1-5 and 8-12) and S-1 group (80-120 mg orally per day by body surface area; days 1-14) over a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), response rate (RR), disease control rate (DCR), and safety. RESULTS: Among 101 patients enrolled, 50 received resminostat+S-1 and 51 received placebo+S-1. Median PFS was 2.9 months for resminostat+S-1 vs. 3.0 months for placebo+S-1 (HR: 1.154, 95% CI: 0.759-1.757, p = 0.502); median OS was 7.8 months vs. 7.5 months, respectively (HR: 1.049, 95% CI: 0.653-1.684, p = 0.834); the RR and DCR were 6.0% vs. 9.8% and 70.0% vs. 78.4%, respectively. Treatment-related adverse events (TrAEs) of grade ≥ 3 occurring more frequently (≥10% difference) in the resminostat+S-1 than in the placebo+S-1 comprised platelet count decreased (18.0% vs. 2.0%) and decreased appetite (16.0% vs. 2.0%). CONCLUSIONS: Resminostat plus S-1 therapy improved neither PFS nor OS for patients with pre-treated BTCs. Addition of resminostat to S-1 was associated with higher incidence of TrAEs, but these were manageable (JapicCTI-183883).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Ácidos Hidroxámicos/uso terapéutico , Ácido Oxónico/uso terapéutico , Sulfonamidas/uso terapéutico , Tegafur/uso terapéutico , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Sistema Biliar/mortalidad , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Método Doble Ciego , Esquema de Medicación , Combinación de Medicamentos , Femenino , Humanos , Ácidos Hidroxámicos/efectos adversos , Japón , Masculino , Persona de Mediana Edad , Ácido Oxónico/efectos adversos , Placebos/uso terapéutico , Compuestos de Platino/uso terapéutico , Supervivencia sin Progresión , Sulfonamidas/efectos adversos , Tegafur/efectos adversos , Adulto Joven , GemcitabinaRESUMEN
We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight patients received IV belinostat days 1-5 and 8-12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m2 bortezomib and 1000 mg/m2 belinostat. One patient with highly refractory MLL-ENL rearranged biphenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with stable disease (SD) for 32 cycles. Whole-exome sequencing revealed no aberrations in the first patient and a hyper-mutator genotype in the second. Eighteen patients had a best response of SD. We conclude that this treatment strategy is feasible but has limited activity in this population. Nevertheless, the factors that predict exceptional responses to this strategy warrant further investigation.
Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib/uso terapéutico , Humanos , Ácidos Hidroxámicos/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Sulfonamidas , Resultado del TratamientoRESUMEN
Epigenetic changes associated with aging have been linked to functional and cognitive deficits in the adult CNS. Histone acetylation is involved in the control of the transcription of plasticity and regeneration-associated genes. The intrinsic axon growth capacity in the CNS is negatively regulated by phosphatase and tensin homolog (Pten). Inhibition of Pten is an effective method to stimulate axon growth following an injury to the optic nerve, corticospinal tract (CST), and rubrospinal tract (RST). Our laboratory has previously demonstrated that the deletion of Pten in aged animals diminishes the regenerative capacity in rubrospinal neurons. We hypothesize that changes in the chromatin structure might contribute to this age-associated decline. Here, we assessed whether Trichostatin A (TSA), a histone deacetylases (HDACs) inhibitor, reverses the decline in regeneration in aged Ptenf/f mice. We demonstrate that HDAC inhibition induces changes in the expression of GAP43 in both young and aged Ptenf/f mice. The regenerative capacity of the RST did not improve significantly in young mice, neither their motor function on the horizontal ladder or cylinder test after TSA treatment for 7 days. Interestingly, TSA treatment in the aged mice worsened their motor function deficits, suggesting that the systemic treatment with TSA might have an overall adverse effect on motor recovery after SCI in aged animals.
Asunto(s)
Envejecimiento/genética , Envejecimiento/fisiología , Axones/metabolismo , Axones/fisiología , Eliminación de Gen , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/farmacología , Histona Desacetilasas/fisiología , Ácidos Hidroxámicos/farmacología , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/genética , Fosfohidrolasa PTEN/genética , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/fisiopatología , Médula Espinal/metabolismo , Animales , Proteína GAP-43/genética , Proteína GAP-43/metabolismo , Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/efectos adversos , Ácidos Hidroxámicos/efectos adversos , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/genéticaRESUMEN
AIMS: The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic. METHODS: We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction. RESULTS: Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m2 /day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease. CONCLUSION: While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.
Asunto(s)
Inhibidores de Histona Desacetilasas/farmacocinética , Ácidos Hidroxámicos/farmacocinética , Hepatopatías/fisiopatología , Hígado/metabolismo , Neoplasias/tratamiento farmacológico , Sulfonamidas/farmacocinética , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/efectos adversos , Infusiones Intravenosas , Hígado/fisiopatología , Hepatopatías/diagnóstico , Hepatopatías/etiología , Masculino , Dosis Máxima Tolerada , Tasa de Depuración Metabólica/fisiología , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/complicaciones , Neoplasias/patología , Índice de Severidad de la Enfermedad , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversosRESUMEN
BACKGROUND: Combined focal adhesion kinase (FAK) and MEK inhibition may provide greater anticancer effect than FAK monotherapy. METHODS: This dose-finding phase Ib study (adaptive 3 + 3 design) determined the maximum tolerated dose (MTD) of trametinib and the FAK inhibitor GSK2256098 in combination. Eligible patients had mesothelioma or other solid tumours with probable mitogen activated protein kinase pathway activation. Adverse events (AEs), dose-limiting toxicities, disease progression and pharmacokinetics/pharmacodynamics were analysed. RESULTS: Thirty-four subjects were enrolled. The GSK2256098/trametinib MTDs were 500 mg twice daily (BID)/0.375 mg once daily (QD) (high/low) and 250 mg BID/0.5 mg QD (low/high). The most common AEs were nausea, diarrhoea, decreased appetite, pruritus, fatigue and rash; none were grade 4. Systemic exposure to trametinib increased when co-administered with GSK2256098, versus trametinib monotherapy; GSK2256098 pharmacokinetics were unaffected by concomitant trametinib. Median progression-free survival (PFS) was 11.8 weeks (95% CI: 6.1-24.1) in subjects with mesothelioma and was longer with Merlin-negative versus Merlin-positive tumours (15.0 vs 7.3 weeks). CONCLUSIONS: Trametinib exposure increased when co-administered with GSK2256098, but not vice versa. Mesothelioma patients with loss of Merlin had longer PFS than subjects with wild-type, although support for efficacy with this combination was limited. Safety profiles were acceptable up to the MTD.
Asunto(s)
Aminopiridinas/administración & dosificación , Proteína-Tirosina Quinasas de Adhesión Focal/genética , Ácidos Hidroxámicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificación , Anciano , Aminopiridinas/efectos adversos , Aminopiridinas/farmacocinética , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Humanos , Ácidos Hidroxámicos/efectos adversos , Ácidos Hidroxámicos/farmacocinética , Masculino , Mesotelioma/tratamiento farmacológico , Mesotelioma/genética , Mesotelioma/patología , Persona de Mediana Edad , Neoplasias/genética , Neoplasias/patología , Supervivencia sin Progresión , Piridonas/efectos adversos , Piridonas/farmacocinética , Pirimidinonas/efectos adversos , Pirimidinonas/farmacocinéticaRESUMEN
Histone deacetylase inhibitors (HDACIs) have demonstrated effectiveness against lymphomas and myelomas in clinical practice. However, common to all currently approved broad-acting HDACIs (panHDACIs) is dose-limiting thrombocytopenia, which has prevented wider use in cancer therapy. Using CD34+ hematopoietic stem cells (HSCs), we show that megakaryocyte (MK) cell maturation and differentiation are impaired by panHDACIs, correlating to clinical thrombocytopenia. Importantly, we demonstrate that inhibitors of class II histone deacetylases (HDACs), including LMK235 and tubacin at clinically relevant concentrations, do not affect MK maturation. Furthermore, we show that HDACI-induced impairment of MK differentiation is associated with reduction of protein levels of the transcription factor GATA-1, but not tubulin hyperacetylation. Finally, we report that panHDACIs trigger a rapid loss of GATA-1 protein via a proteasome-dependent pathway. Our data support the notion that specifically targeting class II HDACs in cancer treatment is a potential strategy that would offer a safer alternative than current panHDACIs.
Asunto(s)
Anilidas/farmacología , Diferenciación Celular/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Megacariocitos/metabolismo , Anilidas/efectos adversos , Antígenos CD34/metabolismo , Línea Celular Tumoral , Factor de Transcripción GATA1/metabolismo , Células Madre Hematopoyéticas/patología , Inhibidores de Histona Desacetilasas/efectos adversos , Humanos , Ácidos Hidroxámicos/efectos adversos , Megacariocitos/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis/efectos de los fármacos , Trombocitopenia/inducido químicamente , Trombocitopenia/metabolismo , Trombocitopenia/patologíaRESUMEN
Histone deacetylases (HDACs) are expressed at increased levels in cells of various malignancies, and the use of HDAC inhibitors has improved outcomes in patients with haematological malignancies (T-cell lymphomas and multiple myeloma). However, they are not as effective in solid tumours. Five agents are currently approved under various jurisdictions, namely belinostat, chidamide, panobinostat, romidepsin and vorinostat. These agents are associated with a range of class-related and agent-specific serious and/or severe adverse effects, notably myelosuppression, diarrhoea and various cardiac effects. Among the cardiac effects are ST-T segment abnormalities and QTc interval prolongation of the electrocardiogram, isolated cases of atrial fibrillation and, in rare instances, ventricular tachyarrhythmias. In order to improve the safety profile of this class of drugs as well as their efficacy in indications already approved and to further widen their indications, a large number of newer HDAC inhibitors with varying degrees of HDAC isoform selectivity have been synthesised and are currently under clinical development. Preliminary evidence from early studies suggests that they may be effective in non-haematological cancers as well when used in combination with other therapeutic modalities, but that they too appear to be associated with the above class-related adverse effects. As the database accumulates, the safety, efficacy and risk/benefit of the newer agents and their indications will become clearer.
Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/metabolismo , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Humanos , Ácidos Hidroxámicos/efectos adversos , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Neoplasias/metabolismo , Sulfonamidas/efectos adversos , Sulfonamidas/farmacología , Sulfonamidas/uso terapéuticoRESUMEN
This open-label, single-arm phase II study examined efficacy, safety, pharmacokinetics, and biomarkers of histone deacetylase (HDAC) inhibitor resminostat in patients with relapsed or refractory Hodgkin lymphoma. Thirty-seven heavily pretreated patients received 600 (19 patients) or 800 mg (18 patients) oral resminostat daily for the initial 5 days of 14-day treatment cycles. Objective response rate (ORR) (primary) was 34% reaching disease control in 54% patients. Most patients (69%) showed reduced tumor size and reduced [18F]-FDG uptake in target lesions (71%). Median progression-free survival (PFS) was 2.3 months (95%CI [1.3; 3.3]) and median overall survival (OS) was 12.5 months (95%CI [9.6; 18.6]). Patients who responded or stabilized under resminostat had a 10-month longer OS than patients who progressed. Efficacy assessment, pharmacodynamics, and exploratory biomarker results followed plasma levels, showed target engagement and epigenetic modulations. Common drug-related adverse events (AEs) were nausea, vomiting, anemia, thrombocytopenia, and fatigue, mainly grade 1 or 2.
Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Ácidos Hidroxámicos/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Biomarcadores , Resistencia a Antineoplásicos , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/farmacocinética , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/etiología , Enfermedad de Hodgkin/mortalidad , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/efectos adversos , Ácidos Hidroxámicos/farmacocinética , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de Positrones , Recurrencia , Retratamiento , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP). RESULTS: Nine patients (3: 400 mg, 6: 600 mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400 mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1 months with monotherapy versus 2.8/11.8 months with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% versus 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% versus 2.4%, p < 0.001). Subgroup analysis revealed that median TTP/OS was 1.5/6.9 months for monotherapy versus 2.8/13.1 months for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 103/mm3). CONCLUSIONS: In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pueblo Asiatico , Carcinoma Hepatocelular/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/uso terapéutico , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/uso terapéutico , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , Administración Oral , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Hepatocelular/patología , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Humanos , Ácidos Hidroxámicos/efectos adversos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/patología , Masculino , Estadificación de Neoplasias , Sorafenib/efectos adversos , Sulfonamidas/efectos adversos , Resultado del TratamientoRESUMEN
This is a phase II study of panobinostat, an oral pan-HDAC inhibitor, combined with rituximab in patients with relapsed diffuse large B cell lymphoma. Panobinostat was administered orally 3 times a week every other week on a 28-day cycle. Rituximab was administered weekly during the first cycle, then on Day 1 of cycles 2 to 6. Patients without disease progression after 6 cycles continued panobinostat monotherapy for up to 6 additional cycles in the absence of disease progression. Eighteen eligible subjects were enrolled, and 18 were evaluable for response. The overall response rate was 11% (90% CI [2%-34%]) with 2 subjects having a partial response. The duration of response in these subjects was 51 and 60 days. Five additional subjects had stable disease with 3 subjects having tumor reduction between 27 and 44%, not meeting criteria for partial response. One subject with stable disease remained on therapy a total of 12 cycles. The most common toxicities while on study were thrombocytopenia (14 patients, 78%); fatigue (11, 61%); anemia (10, 56%); diarrhea (8, 44%); and nausea, lymphopenia, anorexia, and hypophosphatemia (5 each, 28% of patients), the majority of which was grade 2 or less. These data indicate that the combination of panobinostat with rituximab is able to induce responses in a limited number of subjects with relapsed diffuse large B cell lymphoma.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/efectos adversos , Indoles/administración & dosificación , Indoles/efectos adversos , Linfoma de Células B Grandes Difuso/terapia , Masculino , Persona de Mediana Edad , Panobinostat , Recurrencia , Rituximab/administración & dosificación , Rituximab/efectos adversos , Trasplante de Células MadreRESUMEN
PURPOSE: Belinostat is a second-generation histone deacetylase inhibitor (HDI) predominantly metabolized by UGT1A1-mediated glucuronidation. Two common polymorphisms (UGT1A1*28 and UGT1A1*60) were previously associated with impaired drug clearance and thrombocytopenia risk, likely from increased drug exposure. This latter phenomenon has been observed with other HDIs such as abexinostat, panobinostat, romidepsin, and vorinostat. It was the intention of this brief report to expand a population pharmacokinetic (PPK) model to include a pharmacodynamic (PD) model describing the change in platelet levels in patients with cancer administered belinostat as a 48-h continuous intravenous infusion, along with cisplatin and etoposide. METHODS: The PPK/PD model developed here introduced an additional rate constant to a commonly used mechanistic myelosuppression model to better describe the maturation of megakaryocytes into platelets before degradation and a feedback mechanism. The model employed a proportional error model to describe the observed circulating platelet data. RESULTS: Several covariates were explored, including sex, body weight, UGT1A1 genotype status, liver, and kidney function, but none significantly improved the model. Platelet levels rebounded to baseline within 21 days, before the next cycle of therapy. Simulations predicted that higher belinostat drug exposure does cause lower thrombocyte nadirs compared to lower belinostat levels. However, platelet levels rebound by the start of the next belinostat cycle. CONCLUSIONS: This model suggests a q3week schedule allows for sufficient platelet recovery before the next belinostat infusion is optimal.
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Plaquetas/efectos de los fármacos , Ácidos Hidroxámicos/efectos adversos , Ácidos Hidroxámicos/farmacocinética , Modelos Biológicos , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Plaquetas/metabolismo , Plaquetas/patología , Ensayos Clínicos Fase I como Asunto , Simulación por Computador , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/sangre , Inhibidores de Histona Desacetilasas/farmacocinética , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/sangre , Infusiones Intravenosas , Masculino , Sulfonamidas/administración & dosificación , Sulfonamidas/sangreRESUMEN
Drug-resistance is the key reason for the ineffectiveness of chemotherapy in pancreatic cancer. Thus, it is very important to explore the molecular mechanisms of drugresistance and the methods of effective intervention. In the present study, we investigated the effect of tyrphostin B42, also called AG490, on histone deacetylase (HDAC) inhibitor trichostatin A (TSA)induced resistance in pancreatic cancer cells (PCCs). Evidence from phase contrast microscope revealed that TSAresistant cells (PANC1TSA) had higher proliferative activity than nonresistant cells (PANC1). This overproliferative activity induced by TSA may be associated with abnormal activation of JAK2/STAT3 signaling, which can be strengthened by interleukin6 (IL6), a STAT3upstream inducer, resulting in enhanced expression of STAT3-downstream target genes including cMyc, cSrc, HIF1α, and CCND1. In addition, increased expression of Bcl2 mRNA and decreased expression of Bax mRNA in PANC1TSA cells indicated that TSA induced the inhibition of mitochondrial-dependent apoptosis in PCCs. Tyrphostin B42 treatment evidently antagonized the activation of IL6/JAK2/STAT3 in a dosedependent manner. As a result, tyrphostin B42 inhibited the overproliferative activity of PANC1TSA cells, and downregulated the expression of IL6/JAK2/STAT3downstream target genes. Moreover, tyrphostin B42 induced the apoptosis of PCCs by regulating the expression of mitochondrialrelated genes. Therefore, these findings demonstrated that tyrphostin B42 attenuated TSAmediated resistance in PCCs by antagonizing the IL6/JAK2/STAT3 signaling.
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Interleucina-6/genética , Janus Quinasa 2/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Factor de Transcripción STAT3/genética , Tirfostinos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ácidos Hidroxámicos/efectos adversos , Ácidos Hidroxámicos/farmacología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Transducción de Señal/efectos de los fármacosRESUMEN
Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor, which has been widely utilized throughout the cancer research field. SAHA-induced radiosensitization in normal human fibroblasts AG1522 and lung carcinoma cells A549 were evaluated with a combination of γ-rays, proton, and carbon ion exposure. Growth delay was observed in both cell lines during SAHA treatment; 2 µM SAHA treatment decreased clonogenicity and induced cell cycle block in G1 phase but 0.2 µM SAHA treatment did not show either of them. Low LET (Linear Energy Transfer) irradiated A549 cells showed radiosensitization effects on cell killing in cycling and G1 phase with 0.2 or 2 µM SAHA pretreatment. In contrast, minimal sensitization was observed in normal human cells after low and high LET radiation exposure. The potentially lethal damage repair was not affected by SAHA treatment. SAHA treatment reduced the rate of γ-H2AX foci disappearance and suppressed RAD51 and RPA (Replication Protein A) focus formation. Suppression of DNA double strand break repair by SAHA did not result in the differences of SAHA-induced radiosensitization between human cancer cells and normal cells. In conclusion, our results suggest SAHA treatment will sensitize cancer cells to low and high LET radiation with minimum effects to normal cells.
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Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Neoplasias/radioterapia , Fármacos Sensibilizantes a Radiaciones/farmacología , Células A549 , Biomarcadores de Tumor/análisis , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Partículas Elementales/uso terapéutico , Fibroblastos/efectos de los fármacos , Rayos gamma/uso terapéutico , Inhibidores de Histona Desacetilasas/efectos adversos , Humanos , Ácidos Hidroxámicos/efectos adversos , Fotones/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/efectos adversos , VorinostatRESUMEN
Quercetin, a flavonol, displays anti-inflammatory and anti-cancer properties. This study aimed to investigate whether a diet containing 0.1% or 1% quercetin (LQ and HQ, respectively) enhances the anti-tumor effects of trichostatin A (TSA) and prevents muscle wasting induced by TSA. The positive control group received quercetin intraperitoneally (IQ). Three weeks after injecting A549 cells, nude mice were given TSA alone or in combination with quercetin administered orally or intraperitoneally for 16 weeks. Tumor volumes as well as body, muscle and epididymal fat weights were determined during or after the experiment. Quercetin given as a diet supplement dose-dependently enhanced the anti-tumor potency of TSA (p < 0.05). The enhancing effect of HQ was similar to that of IQ. HQ also significantly increased the expression of p53, a tumor suppressor, in tumor tissues compared with the TSA alone group. In addition, TSA-induced loss of gastrocnemius muscle weight was inhibited by oral quercetin in a dose dependent manner; the efficiencies of LQ and HQ were similar to or better than IQ. Moreover, both LQ and HQ decreased TSA-induced activation of Forkhead box O1 (FOXO1), a crucial transcription factor that regulates muscle wasting associated genes. Consistently, LQ and HQ suppressed muscle wasting associated proteins atrophy gene-1 and muscle ring-finger protein-1 expression as well as increased the myosin heavy chain level in the gastrocnemius muscles. Besides, quercetin attenuated TSA-increased oxidative damage and proinflammatory cytokines (p < 0.05). These findings demonstrate that a diet containing 0.1% or 1% quercetin enhances the antitumor effect of TSA and prevents TSA-induced muscle wasting.
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Antineoplásicos/efectos adversos , Ácidos Hidroxámicos/efectos adversos , Atrofia Muscular/prevención & control , Neoplasias/tratamiento farmacológico , Quercetina/administración & dosificación , Animales , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Quimioterapia Combinada , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Ácidos Hidroxámicos/administración & dosificación , Masculino , Ratones , Ratones Desnudos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología , Atrofia Muscular/etiología , Atrofia Muscular/metabolismo , Atrofia Muscular/fisiopatología , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismoRESUMEN
PURPOSE: To translate promising preclinical data on the combination of vorinostat and ixabepilone for metastatic breast cancer (MBC) into clinical trials. METHODS: We conducted a randomized two-arm Phase IB clinical trial of ascending doses of vorinostat and ixabepilone in prior -treated MBC patients. To determine the maximum tolerated dose (MTD), 37 patients were randomized to schedule A: every-3-week ixabepilone + vorinostat (days 1-14), or schedule B: weekly ixabepilone + vorinostat (days 1-7; 15-21) Pharmacokinetics were assessed. Nineteen additional patients were randomized to schedule A or B and objective response rate (ORR), clinical benefit rate (CBR), toxicity, progression-free survival (PFS), and overall survival (OS) were assessed. RESULTS: The schedule A MTD was vorinostat 300 mg daily (days 1-14), ixabepilone 32 mg/m2 (day 2); 21-day cycle 27% dose-limiting toxicities (DLTs). The schedule B MTD was vorinostat 300 mg daily (days 1-7; 15-21), ixabepilone 16 mg/m2 (days 2, 9, 16); 28-day cycle; no DLTs. Vorinostat and ixabepilone clearances were 194 L/h and 21.3 L/h/m2, respectively. Grade 3 peripheral sensory neuropathy was reported in 8% (A) and 21% (B) of patients. The ORR and CBR were 22 and 22% (A); 30 and 35% (B). Median PFS was 3.9 (A) and 3.7 (B) months. OS was 14.8 (A) and 17.1 (B) months. CONCLUSIONS: We established the MTD of vorinostat and ixabepilone. This drug combination offers a novel therapy for previously treated MBC patients. The potential for lower toxicity and comparable efficacy compared to current therapies warrants further study.