Early tumor progression associated with enhanced EGFR signaling with bortezomib, cetuximab, and radiotherapy for head and neck cancer
| Autor: | John J. Wright, Mukesh K. Nyati, Nicole L. Simone, Yoshio Arai, Aarif Ahsan, Athanassios Argiris, Susan F. Rudy, Austin G. Duffy, Vishnu R. Kannabiran, Carter Van Waes, Nanette Suksta, Susmita G. Ramanand, Xinping Yang, Minyoung Jang, T. Cooley-Zgela, Zhong Chen, Shivaani Kummar, Seungwon Kim |
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| Rok vydání: | 2011 |
| Předmět: |
Oncology
Male Cancer Research Pathology medicine.medical_specialty medicine.medical_treatment Cetuximab Apoptosis Antibodies Monoclonal Humanized Article Bortezomib Internal medicine Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Mucositis Biomarkers Tumor Humans Protease Inhibitors business.industry Squamous Cell Carcinoma of Head and Neck Head and neck cancer Antibodies Monoclonal Middle Aged medicine.disease Boronic Acids Combined Modality Therapy Radiation therapy ErbB Receptors Treatment Outcome Tumor progression Head and Neck Neoplasms Pyrazines Proteasome inhibitor Carcinoma Squamous Cell Disease Progression Cytokines Female Radiotherapy Intensity-Modulated business Progressive disease medicine.drug Signal Transduction Transcription Factors |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 17(17) |
| ISSN: | 1557-3265 |
| Popis: | Purpose: A phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy. Experimental Design: Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m2) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1. Results: Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (progression-free survival = 4.8 months; 95% CI, 2.6–6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m2, without dose-limiting toxicities; one patient treated at 1.3 mg/m2 was taken off study due to recurring cetuximab infusion reaction and progressive disease (PD). Expected grade 3 toxicities included radiation mucositis (n = 4), dermatitis (n = 4), and rash (n = 1). SCCHN-related cytokines increased in serial serum specimens of patients developing PD (P = 0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1. Conclusions: Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination. Clin Cancer Res; 17(17); 5755–64. ©2011 AACR. |
| Databáze: | OpenAIRE |
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