Preclinical Tumor Model Systems
Irradiation is an integral part of head neck squamous cell carcinoma (HNSCC) therapy. However, tumors frequently develop resistance which is an important limiting factor for treatment success. Preclinical model systems are needed to identify resistance mechanisms in this heterogeneous entity.
Numerous clinical and experimental studies give evidence that ionizing radiation causes compensatory upregulation of intracellular signaling cascades resulting in cancer cell survival. We previously demonstrated irradiation-induced activation of MEK/ERK and PI3K/AKT/mTOR pathways in tumor cells. It was hypothesized that complex interactions between these cascades may account for treatment failure.
Within the proposed project molecular principles of the interplay between MEK/ERK, PI3K/AKT/mTOR, as well as other cascades in the course of radiotherapy will be elucidated in multi-disciplinary approaches by the use of established HNSCC cell lines, ex vivo tissue culture models and patient samples, and models for innovative and individualized treatment concepts will be generated. Subsequently, the established models will be validated and optimized by direct inhibition of central points of interaction of relevant signaling pathways by combined application of pharmacologic inhibitors and irradiation in HNSCC cell lines and ex vivo tissue culture models.
An efficient translation of the experimental data into clinical studies will be pursued.