Stem Cell Therapies of Head and Neck Squamous Cell Carcinomas

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Head and neck cancers are a heterogeneous group of tumors, which occur in the oral cavity, the oropharynx, larynx, hypopharynx, the nasal cavity and paranasal sinus, including the salivary glands. The majority of head and neck cancers are squamous cell carcinomas, HNSCCs. Annually, around 600.000 patients are newly diagnosed, making HNSCC the fifth most frequent malignant cancer worldwide. There exists a lack of therapies to treat HNSCC patients. Radio and chemotherapies and EGFR antibody therapies have limited effects and are often accompanied by impairing side effects. Salivary gland squamous cell carcinomas are also difficult to treat, because of their aggression and production of lymphogenic metastases. In the proposed project, we aim to establish new procedures to interfere with the formation of head and neck squamous cell carcinomas. It is a twinning study that involves two groups located in Duesseldorf and Berlin. Single and combined therapies using small molecule inhibitors against Wnt, Mll1, Met, Shp2 and CXCR4 will be examined in mouse and human tumor cells and tumor models. The focus of this project is not basic research, which the Birchmeier lab has performed for many years, but translational research and application of the basic findings. This project will thus prepare for clinical trials to be performed in the Schipper lab and the HNO Clinic in Duesseldorf, that ultimately aim to improve treatments for cancer patients. Medically, this is extremely important, since the options for targeted therapies in head and neck cancers are presently minimal. The following experiments are planned. 1. The effects of selected small molecule inhibitors of Met, Shp2 und CXCR4 and inhibitor combinations will be examined on proliferation, differentiation and gene expression in sphere cultures of mouse salivary gland cancer stem cells. Group Berlin, Birchmeier. 2. The effects of selected inhibitors of Wnt, Mll1, Met, Shp2 and CXCR4 signaling will be tested in human HNSCC cell lines that grow in sphere culture. Group Duesseldorf, Schipper. 3. Selected inhibitors and combinations against Wnt, Mll1, Met, Shp2 and CXCR4 will be tested following transplantation of mouse salivary gland cancer stem cells into immune deficient mice. Group Berlin, Birchmeier. 4. Cancer stem cell like cells that grow as spheres from human HPV positive and HPV negative HNSCC patients will be examined for the response to selected inhibitors. Group Duesseldorf, Schipper. 5. Inhibitors and inhibitor combinations, which have been successfully used in the cell culture experiments, will be examined in mice on transplanted human cancer stem cells like cells obtained from HNSCC patients. Group Berlin, Birchmeier. 6. Gene expression signatures of therapy responders and non responders of HPV positive und HPV negative HNSCC cells will be determined after transplantation. Groups Berlin and Duesseldorf, Birchmeier and Schipper.