Publications (2)11.46 Total impact
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Article: Early tumor progression associated with enhanced EGFR signaling with bortezomib, cetuximab, and radiotherapy for head and neck cancer.
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ABSTRACT: 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. 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. 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. 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.Clinical Cancer Research 08/2011; 17(17):5755-64. · 7.74 Impact Factor -
Article: EGFR-PI3K-AKT-mTOR signaling in head and neck squamous cell carcinomas: attractive targets for molecular-oriented therapy.
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ABSTRACT: Recent advances in the understanding of the oncogenesis of head and neck squamous cell carcinomas (HNSCC) have revealed multiple dysregulated signaling pathways. One frequently altered axis is the EGFR-PI3K-Akt-mTOR pathway. This pathway plays a central role in numerous cellular processes including metabolism, cell growth, apoptosis, survival and differentiation, which ultimately contributes to HNSCC progression. Books, journals, databases and websites have been searched to provide a current review on the subject. This article reviews the current understanding of EGFR-PI3K-Akt-mTOR signaling in HNSCC, including the impact of both genetic and epigenetic alterations. This review further highlights the potential of targeting this signaling cascade as a promising therapeutic approach in the treatment of HNSCC. Genetic alterations of several nodes within this pathway, including both genetic and epigenetic changes, leading to either oncogene activation or inactivation of tumor suppressors have frequently been implicated in HNSCC. Consequently, drugs that target the central nodes of this pathway have become attractive for molecular oriented cancer therapies. Numerous preclinical and clinical studies are being performed in HNSCC; however, more studies are still needed to better understand the biology of this pathway.Expert opinion on therapeutic targets 01/2011; 15(1):63-74. · 3.72 Impact Factor
