Open AccessXenograft assessment of predictive biomarkers for standard head and neck cancer therapies
Author(s) -
Stein Andrew P.,
Swick Adam D.,
Smith Molly A.,
Blitzer Grace C.,
Yang Robert Z.,
Saha Sandeep,
Harari Paul M.,
Lambert Paul F.,
Liu Cheng Z.,
Kimple Randall J.
Publication year - 2015
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.387
Subject(s) - cetuximab , medicine , biomarker , head and neck squamous cell carcinoma , oncology , head and neck cancer , tissue microarray , epidermal growth factor receptor , egfr inhibitors , radiation therapy , ercc1 , predictive marker , cisplatin , cancer , cancer research , chemotherapy , biology , colorectal cancer , dna repair , biochemistry , nucleotide excision repair , gene
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 ( ERCC 1). 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 ERCC 1 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 .