Summary

The translational research laboratory headed by Inge Tinhofer-Keilholz is focusing in the analysis of resistance mechanisms of targeted and non-targeted therapy and the identification of prognostic / predictive biomarkers in head and neck cancer. In the last DKTK period, we focused on molecular mechanisms of treatment failure in SCCHN. In cooperation with the group of Ulrich Keilholz, we evaluated the diagnostic potential of circulating tumor cells as ‘liquid biopsies’ for geno- and phenotypic tumor cell characterization. We have established syngeneic SCCHN cell line models of acquired resistance to cisplatin or cetuximab and have generated single-cell derived clones with primary resistance to cisplatin, cetuximab and irradiation which can be used for novel drug screening. Within the joint funding project of the DKTK Radiation Oncology Group (ROG) we used mutational profiling by targeted next-generation sequencing (NGS) of archival formalin-fixed paraffin-embedded (FFPE) tumor specimens for the molecular characterization of SCCHN cohorts. We also studied the interference of mutational patterns with radio-/chemosensitivity, patient age, the inflammatory signature of tumors and the expression of immune checkpoints.
Recently, we used the Nanostring technology for assessment of immune-cell related mRNA expression signatures in tumor specimens from head and neck carcinoma patients. We established a 5-gene signature which is highly predictive for the efficacy of cisplatin-based chemoradiation in oropharyngeal carcinomas. Currently, this signature is prospectively validated in the DKTK-ROG biomarker study HNprädBio.
In a pilot study, the mutational profiles of paired tumor samples (primary, R/M lesions) from 10 patients with locally advanced SCCHN who progressed after concurrent chemoradiation (CTRX) were established by NGS targeting the exonic regions of 327 genes. We could demonstrate that treatment-induced clonal selection after CRTX frequently occurs in SCCHN but was limited to only few gene alterations associated with an aggressive phenotype (Tinhofer et al, unpublished data). This result is rather surprising given CRTX being a DNA-damaging regimen with inherent risk of de-novo mutagenesis and abundant time for clonal tumor evolution. Further investigations of spatial intratumoral heterogeneity and clonal evolution in larger patient cohorts are ongoing for improving our understanding of treatment resistance and disease progression in SCCHN.