title: Xenograft assessment of predictive biomarkers for standard head and neck cancer therapies.
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.
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 53706.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Stein
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 53706.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Swick
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 53706.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 53706.
authors.forename: Grace C
authors.initials: GC
authors.lastname: Blitzer
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 53706.
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Yang
authors.affiliation: Department of Biostatistics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 53706.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Saha
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 53706.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harari
authors.affiliation: Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 53706.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
authors.affiliation: Department of Pathology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 53706.
authors.forename: Cheng Z
authors.initials: CZ
authors.lastname: Liu
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 53706.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Kimple
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D015415:Biomarkers; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage / Q000494:pharmacology; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004720:Endonucleases / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000628:therapy / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011878:Radiotherapy; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D004268:DNA-Binding Proteins; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C071447:ERCC1 protein, human; D004720:Endonucleases; D000068818:Cetuximab; D002945:Cisplatin
keywords: HNSCC; HPV; Head and neck cancer; predictive biomarkers; xenografts