Abstract 2434: Identification of new treatment options for platinum-resistant head and neck cancer in a panel of broadly characterized patient-derived xenografts.
Authors: Konrad Klinghammer, Jan D Raguse, Moritz Siedmann, Michael Becker, Ulrich Keilholz, Jens Hoffmann, Iduna Fichtner
Journal: Cancer Research (2013)

Abstract Background-Aims: Cell lines and thereof established xenografts have a limited value for preclinical drug evaluation and biomarker analysis due to clonal selection and cellular dedifferentiation. We started establishing a large panel of patient derived xenografts from head and neck squamous cell carcinomas displaying the heterogeneity of this disease. Using these models we evaluate sensitivity to standard treatment, search for predictive biomarkers and test the sensitivity of experimental drugs and new treatment approaches. Methods: Specimens from head and neck tumor surgery were transplanted subcutaneously to immunodeficient mice within 24 hours. In case of engraftment, after 3rd passage, groups of 6 mice were treated with 5-FU, MTX, Cetuximab, Carboplatin, Docetaxel and in addition with the not yet approved drug Everolimus. Treatment was applied for 3 weeks. Response to treatment was evaluated by comparing growth inhibition of treated tumors in relation to a control group. Patient tumors and derived xenografts were evaluated for HPV status by immunohistochemical staining of p16INK4A and detection of HPV-16 E6 and E7 viral DNA by PCR. Primary tumor and the derived xenografts are screened for common oncogenic mutations using the Illumina TruSeq Amplicon - Cancer Panel. In addition transcription of mTOR pathway members were analyzed in more detail using RT-PCR and protein expression analysis. Results: In total, 70 tumor samples were transplanted resulting in 26 stably growing patient derived xenografts, 23 failed and 21 remain presently ongoing. Tumors remained histologically similar through several passages. Response to treatment varied considerably. We observed a remarkably large number of platin resistant tumors (9/11) in our study group. With our approach to identify alternative treatment options, we observed with the mTOR inhibitor everolimus a significant growth inhibition in 7 of 9 platin resistant tumors. Correlation of response with mutations in common oncogenes will be evaluated by sequencing and gene expression studies. Conclusion: Using newly developed patient derived xenografts of head and neck squamous cell carcinomas we identified a high sensitivity to the mTOR inhibitor everolimus. These results demonstrate that these models provide an excellent tool for preclinical drug and biomarker evaluation, systems biology and provide rationale hypotheses for further clinical trials. Citation Format: Konrad Klinghammer, Jan D Raguse, Moritz Siedmann, Michael Becker, Ulrich Keilholz, Jens Hoffmann, Iduna Fichtner. Identification of new treatment options for platinum-resistant head and neck cancer in a panel of broadly characterized patient-derived xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2434. doi:10.1158/1538-7445.AM2013-2434