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1.
J Hepatol ; 65(2): 280-8, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26952006

RESUMO

BACKGROUND & AIMS: No established therapies for patients with hepatocellular carcinoma (HCC) and progression on first-line sorafenib treatment currently exist. This phase I/II trial investigated safety, pharmacokinetics and potential biomarkers of the histone deacetylase inhibitor resminostat and a combination therapy with resminostat and sorafenib. METHODS: Patients with HCC and radiologically confirmed progression on sorafenib were treated in an exploratory, multi-center, open-label, uncontrolled, non-randomized, parallel group phase I/II study. In the combination group (n=38) four dose levels ranged from daily 200 to 600mg resminostat plus 400 to 800mg sorafenib. The monotherapy group (n=19) received 600mg resminostat. RESULTS: 57 patients received treatment. Most common adverse events were gastrointestinal disorders, thrombocytopenia and fatigue. Median maximal histone deacetylase inhibition and highest increase in H4-acetylation matched Tmax of resminostat. Sorafenib or the Child-Pugh score did not affect typical pharmacokinetics characteristics of resminostat. Efficacy assessment as progression-free survival-rate after 6 treatment cycles (12weeks, primary endpoint) was 12.5% for resminostat and 62.5% for resminostat plus sorafenib. Median time to progression and overall survival were 1.8 and 4.1months for resminostat and 6.5 and 8.0months for the combination, respectively. Zinc finger protein 64 (ZFP64) baseline expression in blood cells was found to correlate with overall survival. CONCLUSIONS: The combination of sorafenib and resminostat in HCC patients was safe and showed early signs of efficacy. Sorafenib did not alter the pharmacokinetic profile of resminostat or its histone deacetylase inhibitory activity in vivo. A prognostic and potentially predictive role of ZFP64 for treatment with resminostat should be further investigated in HCC and possibly other cancer indications. LAY SUMMARY: No established therapy for patients with advanced hepatocellular carcinoma and progression under first-line systemic treatment with sorafenib currently exists. Epigenetic modulation by inhibition of histone deacetylases might be able to overcome therapy resistance. This exploratory phase I/II clinical study in patients with radiologically confirmed progression under first-line treatment with sorafenib investigated the histone deacetylases inhibitor resminostat as single agent or in combination with continued application of sorafenib. CLINICAL TRIAL REGISTRATION: The clinical trial has been registered at www.clinicaltrials.gov as NCT00943449.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Ácidos Hidroxâmicos , Niacinamida/análogos & derivados , Compostos de Fenilureia , Sorafenibe , Sulfonamidas
2.
Nat Cell Biol ; 6(6): 507-14, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15146192

RESUMO

Tumour cell invasiveness is crucial for cancer metastasis and is not yet understood. Here we describe two functional screens for proteins required for the invasion of fibrosarcoma cells that identified the molecular chaperone heat shock protein 90 (hsp90). The hsp90 alpha isoform, but not hsp90 beta, is expressed extracellularly where it interacts with the matrix metalloproteinase 2 (MMP2). Inhibition of extracellular hsp90 alpha decreases both MMP2 activity and invasiveness. This role for extracellular hsp90 alpha in MMP2 activation indicates that cell-impermeant anti-hsp90 drugs might decrease invasiveness without the concerns inherent in inhibiting intracellular hsp90.


Assuntos
Membrana Celular/metabolismo , Matriz Extracelular/metabolismo , Fibrossarcoma/fisiopatologia , Proteínas de Choque Térmico HSP90/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Invasividade Neoplásica/fisiopatologia , Membrana Basal/metabolismo , Sítios de Ligação/fisiologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Fibrossarcoma/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Humanos , Ligação Proteica/fisiologia , Mapeamento de Interação de Proteínas , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína/fisiologia , Proteômica
3.
Leuk Lymphoma ; 60(3): 675-684, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30160566

RESUMO

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.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Ácidos Hidroxâmicos/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Biomarcadores , Resistencia a Medicamentos Antineoplásicos , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/farmacocinética , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/etiologia , Doença de Hodgkin/mortalidade , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Ácidos Hidroxâmicos/farmacocinética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Recidiva , Retratamento , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Resultado do Tratamento , Adulto Jovem
4.
Photochem Photobiol ; 81(2): 358-66, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15623352

RESUMO

Chromophore-assisted laser inactivation (CALI) is a light-mediated technique used to selectively inactivate proteins of interest to elucidate their biological function. CALI has potential applications to a wide array of biological questions, and its efficiency allows for high-throughput application. A solid understanding of its underlying photochemical mechanism is still missing. In this study, we address the CALI mechanism using a simplified model system consisting of the enzyme beta-galactosidase as target protein and the common dye fluorescein. We demonstrate that protein photoinactivation is independent from dye photobleaching and provide evidence that the first singlet state of the chromophore is the relevant transient state for the initiation of CALI. Furthermore, the inactivation process was shown to be dependent on oxygen and likely to be based on photooxidation of the target protein via singlet oxygen. The simple model system used in this study may be further applied to identify and optimize other CALI chromophores.


Assuntos
Lasers , beta-Galactosidase/antagonistas & inibidores , Absorção , Corantes/química , Fluoresceínas/química , Fluoresceínas/efeitos da radiação , Luz , Modelos Químicos , Oxigênio/química , Fotoquímica , Oxigênio Singlete/efeitos da radiação , Fatores de Tempo , beta-Galactosidase/química , beta-Galactosidase/efeitos da radiação
5.
Mol Ther Oncolytics ; 2: 15019, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27119111

RESUMO

Epigenetic therapies such as histone deacetylase inhibitors (HDACi) not only have the capability to decrease tumor cell proliferation and to induce tumor cell death but also to silence antiviral response genes. Here, we investigated whether the combination of an oncolytic measles vaccine virus (MeV) with the novel oral HDACi resminostat (Res), being in clinical testing in patients with hepatocellular carcinoma (HCC), results in an enhanced efficacy of this epi-virotherapeutic approach compared to any of the two corresponding monotherapies. When testing a panel of human hepatoma cell lines, we found (i) a significantly improved rate of primary infections when using oncolytic MeV under concurrent treatment with resminostat, (ii) a boosted cytotoxic effect of the epi-virotherapeutic combination (Res + MeV) with enhanced induction of apoptosis, and, quite importantly, (iii) an absence of any resminostat-induced impairment of MeV replication and spread. Beyond that, we could also show that (iv) resminostat, after hepatoma cell stimulation with exogenous human interferon (IFN)-ß, is able to prevent the induction of IFN-stimulated genes, such as IFIT-1. This finding outlines the possible impact of resminostat on cellular innate immunity, being instrumental in overcoming resistances to MeV-mediated viral oncolysis. Thus, our results support the onset of epi-virotherapeutic clinical trials in patients exhibiting advanced stages of HCC.

6.
Drug Discov Today ; 7(18 Suppl): S136-42, 2002 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12546880

RESUMO

Identifying the right target for drug development is a critical bottleneck in the pharmaceutical and biotech industries. The genomics revolution has shifted the problem from a scarcity of targets to a surplus of putative drug targets. As the validity of a target cannot be simply inferred from correlative data, the key is confirmation of the causative role of a gene product in a particular disease. It should therefore be recognized that an effective therapeutic strategy requires an appropriate target validation technology to verify the right target.


Assuntos
Avaliação Pré-Clínica de Medicamentos/tendências , Biotecnologia/tendências , Avaliação Pré-Clínica de Medicamentos/métodos , Indústria Farmacêutica/tendências , Genômica , Fenótipo , Proteínas/química , Proteínas/genética , Reprodutibilidade dos Testes , Robótica
7.
IDrugs ; 6(3): 203-6, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12838986

RESUMO

Over a decade of astonishing developments, genomics and proteomics have promised a fundamentally new approach to drug discovery. Although there has been an undeniable increase in the range of potential targets available, this has not led to an increased output of the drug discovery pipeline into the clinic. With tighter markets and increasing competition, the major pharmaceutical companies are under intense pressure to achieve rapid, concrete delivery of those early promises, but there remain acute problems in the genes-to-drugs pipeline. This meeting showcased a range of novel approaches from proteomics and bioinformatics to address these problems. A common theme in the range of proteomics offerings was the prioritization of potential novel targets on the basis of their accessibility to drugs and their functional link to disease phenotypes. Informatics and in silico offerings also concentrated on fast, accurate, drug-focused workflows built on large integrative databases and novel data-mined algorithms.


Assuntos
Genoma , Genômica/métodos , Tecnologia Farmacêutica/métodos , Animais , Genômica/tendências , Humanos , Proteômica/métodos , Proteômica/tendências , Tecnologia Farmacêutica/tendências
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