Article

Serum biomarkers as potential predictors of antitumor activity of cetuximab-containing therapy for locally advanced head and neck cancer

Head and Neck Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States.
Oral Oncology (Impact Factor: 3.03). 08/2011; 47(10):961-6. DOI: 10.1016/j.oraloncology.2011.07.034
Source: PubMed

ABSTRACT We sought to identify biomarkers of antitumor activity in patients with locally advanced head and neck cancer treated with therapy containing cetuximab, an epidermal growth factor receptor (EGFR) inhibitor. Patients with stage III-IVB head and neck cancer received cisplatin, docetaxel, and cetuximab (TPE) followed by radiotherapy, cisplatin, and cetuximab (XPE) and maintenance cetuximab in a phase II clinical trial. Serum and tissue biomarkers were examined for treatment-related changes and for association with clinical outcomes. Concentrations of 31 cytokines, chemokines and growth factors were measured before and after 3 cycles (9 weeks) of induction TPE using multi-analyte immunobead-based profiling (Luminex Corp., Austin, TX), with selected analytes validated by a single analyte enzyme-linked immunosorbent assay. Tumor biomarkers included phosphorylated signal transducer and activator of transcription-3 (pSTAT3), EGFR and human papillomavirus (HPV). Thirty-one patients had baseline biomarkers and 25 had paired samples, pre- and post-TPE. Adjusting for false discovery, 14 analytes including MCP1c, IP-10, Leptin, interleukin (IL)-5, Eotaxin, IL-6, G-CSF, CXCL5 changed significantly post TPE induction. Serum vascular endothelial growth factor (VEGF) and IL-6 levels were associated with tumor response as assessed by positron emission tomography and progression-free survival, however, the association was not significant after adjustment for false discovery. Analytes were not associated with toxicities, smoking history, HPV status, EGFR amplification, or pSTAT3 tumor protein levels. Baseline serum biomarkers, in particular VEGF and IL-6, were identified as potentially useful prognostic markers of cetuximab-containing therapy. Validation is warranted in future studies specifically designed to detect biomarker associations.

Download full-text

Full-text

Available from: Sufi Mary Thomas, May 06, 2014
0 Followers
 · 
123 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite recent advances in melanoma therapy, disseminated melanoma still lacks effective treatment, and recurrence of the tumor frequently occurs, even after high-dose chemotherapy. The mechanisms responsible for this chemoresistance or for the formation of new relapses remain poorly understood. Using a human 'model', in which the isolated limb is perfused with high doses of the chemotherapeutic melphalan (ILP), we identified a five-gene set (ATF3, CYR61, IER5, IL6, and PTGS2) of stress-induced genes that was consistently upregulated after ILP in all in-transit metastatic melanoma samples as well as in three melphalan-treated melanoma cell lines. Early post-ILP relapses retained these elevated expressions, whereas the expression of these genes returned to their original levels in late post-ILP recurrences. In addition, we identified upregulation of these genes in the A375 cell line's side population (SP) and melanospheres, established methods to enrich for candidate cancer stem cells (CSCs), which are considered chemoresistant and tumorigenic, and thus proposed to be responsible for tumor relapse. Our data identify an immediate and short-term upregulation of early stress-responsive genes that are potentially linked to chemoresistance and CSCs.
    Pigment Cell & Melanoma Research 04/2012; 25(4):454-65. DOI:10.1111/j.1755-148X.2012.01004.x · 5.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nanoantibodies (single-domain antibodies, nanobodies) derived from noncanonical single-chain immunoglobulins provide an attractive tool for in vitro and in vivo diagnostics as well as for development of targeted drugs for clinical use. Nanoantibodies against several clinically important targets have been developed and are actively investigated. However, no development of nanoantibodies against vascular endothelial growth factor VEGF-A(165) has been reported. We describe here the generation of nanoantibodies derived from single-chain Bactrian camel immunoglobulins directed against VEGF-A(165). We demonstrate that these nanoantibodies are suitable for enzyme-linked immunoassay to quantify human VEGF-A(165) as well as for blocking its activity. Our results provide a basis for diagnostic kit development for quantification of VEGF-A(165), which emerges as a biomarker useful in various pathological conditions. In addition, the nanoantibodies might be used for development of therapeutic molecules targeting VEGF-A(165)-dependent pathological neoangiogenesis.
    Biochemistry (Moscow) 06/2012; 77(6):659-65. DOI:10.1134/S0006297912060132 · 1.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVES: PRAME (Preferentially Expressed Antigen in Melanoma) is a tumor-associated antigen recognized by immunocytes, and it induces cytotoxic T cell-mediated responses in melanoma. PRAME expression in tumors interferes with retinoic acid receptor (RAR) signaling thus promoting tumor progression. Here, we study PRAME expression in head and neck squamous cell carcinoma (HNSCC) to determine its potential clinical significance. MATERIALS AND METHODS: PRAME expression in HNSCC was evaluated by immunohistochemistry in tissue microarrays of primary tumors (n=53), metastatic lymph nodes (n=8) and normal oral mucosa (n=11). Biopsies of dysplastic oral lesions (n=12) were also examined. PRAME expression levels in tissues were correlated with markers of poor prognosis in HNSCC. PRAME mRNA in HNSCC cell lines and in normal immortalized human keratinocytes (HaCaT cell line) was measured by qRT-PCR, and the protein expression by flow cytometry and western blots. RESULTS: PRAME was expressed in HNSCC cell lines and HNSCC lesions. PRAME expression in dysplastic mucosa was variable. No or only weak expression was found in normal cells or tissues. PRAME expression levels significantly correlated with the tumor grade, size, nodal involvement and the clinical status of HNSCC patients. CONCLUSIONS: Elevated PRAME expression associates with clinicopathologic markers of poor outcome in HNSCC and might identify potential candidates with pre-cancerous lesions for chemoprevention with retinoids.
    Oral Oncology 08/2012; 49(2). DOI:10.1016/j.oraloncology.2012.08.005 · 3.03 Impact Factor