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Xenograft assessment of predictive biomarkers for standard head and neck cancer therapies.
- Source :
-
Cancer medicine [Cancer Med] 2015 May; Vol. 4 (5), pp. 699-712. Date of Electronic Publication: 2015 Jan 26. - Publication Year :
- 2015
-
Abstract
- Head and neck squamous cell carcinoma (HNSCC) remains a challenging cancer to treat with overall 5-year survival on the order of 50-60%. Therefore, predictive biomarkers for this disease would be valuable to provide more effective and individualized therapeutic approaches for these patients. While prognostic biomarkers such as p16 expression correlate with outcome; to date, no predictive biomarkers have been clinically validated for HNSCC. We generated xenografts in immunocompromised mice from six established HNSCC cell lines and evaluated response to cisplatin, cetuximab, and radiation. Tissue microarrays were constructed from pre- and posttreatment tumor samples derived from each xenograft experiment. Quantitative immunohistochemistry was performed using a semiautomated imaging and analysis platform to determine the relative expression of five potential predictive biomarkers: epidermal growth factor receptor (EGFR), phospho-EGFR, phospho-Akt, phospho-ERK, and excision repair cross-complementation group 1 (ERCC1). Biomarker levels were compared between xenografts that were sensitive versus resistant to a specific therapy utilizing a two-sample t-test with equal standard deviations. Indeed the xenografts displayed heterogeneous responses to each treatment, and we linked a number of baseline biomarker levels to response. This included low ERCC1 being associated with cisplatin sensitivity, low phospho-Akt correlated with cetuximab sensitivity, and high total EGFR was related to radiation resistance. Overall, we developed a systematic approach to identifying predictive biomarkers and demonstrated several connections between biomarker levels and treatment response. Despite these promising initial results, this work requires additional preclinical validation, likely involving the use of patient-derived xenografts, prior to moving into the clinical realm for confirmation among patients with HNSCC.<br /> (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Subjects :
- Animals
Antineoplastic Agents administration & dosage
Antineoplastic Agents pharmacology
Biomarkers
Cell Line, Tumor
Cetuximab administration & dosage
Cetuximab pharmacology
Cisplatin administration & dosage
Cisplatin pharmacology
DNA-Binding Proteins metabolism
Disease Models, Animal
Endonucleases metabolism
ErbB Receptors metabolism
Extracellular Signal-Regulated MAP Kinases metabolism
Female
Head and Neck Neoplasms pathology
Head and Neck Neoplasms therapy
Head and Neck Neoplasms virology
Humans
Immunohistochemistry
Mice
Prognosis
Proto-Oncogene Proteins c-akt metabolism
Radiotherapy
Signal Transduction drug effects
Signal Transduction radiation effects
Xenograft Model Antitumor Assays
Head and Neck Neoplasms metabolism
Head and Neck Neoplasms mortality
Subjects
Details
- Language :
- English
- ISSN :
- 2045-7634
- Volume :
- 4
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cancer medicine
- Publication Type :
- Academic Journal
- Accession number :
- 25619980
- Full Text :
- https://doi.org/10.1002/cam4.387