Phase I trial of induction histone deacetylase and proteasome inhibition followed by surgery in non-small-cell lung cancer.
J Thorac Oncol
; 7(11): 1683-90, 2012 Nov.
Article
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| MEDLINE
| ID: mdl-23059775
ABSTRACT
INTRODUCTION:
Despite complete surgical resection survival in early-stage non-small-cell lung cancer (NSCLC) remains poor. On the basis of prior preclinical evaluations, we hypothesized that combined induction proteasome and histone deacetylase inhibitor therapy, followed by tumor resection, is feasible.METHODS:
A phase I clinical trial using a two-staged multiple-agent design of bortezomib and vorinostat as induction therapy followed by consolidative surgery in patients with NSCLC was performed. Standard toxicity and maximum tolerated dose were examined. Pre- and post-treatment tumor gene-expression arrays were performed and analyzed. Pre- and post-treatment fluorodeoxyglucose-positron emission tomography imaging was used to assess tumor metabolism. Finally, serum 20S proteasome levels were analyzed with enzyme-linked immunosorbent assay, and selected intratumoral proteins were assessed by immunohistochemistry.RESULTS:
Of the 34-four patients providing written consent to participate in the trial, 21 were enrolled. One patient withdrew early because of disease progression. The maximum tolerated dose was bortezomib 1.3 mg/m and vorinostat 300 mg twice daily. There were grade III dose-limiting toxicities of fatigue and hypophosphatemia, which were self-limited. There was no mortality. Thirty percent of patients (6 of 20) had more than 60% histologic necrosis of their tumor after treatment, with two having 90% or more tumor necrosis. Tumor metabolism, 20S proteasome activity, and specific protein expression did not demonstrate consistent results. Gene-expression arrays comparing pre- and post-therapy NSCLC specimens revealed robust intratumoral changes in specific genes.CONCLUSIONS:
Induction bortezomib and vorinostat therapy followed by surgery in patients with operable NSCLC is feasible. Correlative gene-expression studies suggest new targets and cell-signaling pathways that may be important in modulating this combined therapy.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Carcinoma de Células Escamosas
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Adenocarcinoma
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Protocolos de Quimioterapia Combinada Antineoplásica
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Carcinoma de Células Grandes
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Carcinoma de Pulmón de Células no Pequeñas
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Complejo de la Endopetidasa Proteasomal
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Histona Desacetilasas
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Neoplasias Pulmonares
Tipo de estudio:
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Aged80
Idioma:
En
Revista:
J Thorac Oncol
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos