Stem Cell Therapies of Head and Neck Squamous Cell Carcinomas

头颈部癌是一组异质性肿瘤，发生在口腔、口咽、喉、下咽、鼻腔和副鼻窦，包括唾液腺。大多数头颈部癌症是鳞状细胞癌，即HNSCC。每年约有600.000名新诊断的患者，使人类非小细胞肺癌成为全球第五大常见的恶性肿瘤。目前尚缺乏治疗HNSCC患者的方法。放化疗和EGFR抗体治疗的效果有限，而且常常伴随着不良反应。唾液腺鳞状细胞癌也很难治疗，因为它们具有侵袭性并产生淋巴转移。在拟议的项目中，我们的目标是建立新的程序来干预头颈部鳞状细胞癌的形成。这是一项双胞胎研究，涉及杜塞尔多夫和柏林的两个小组。针对Wnt、Mll1、Met、Shp2和CXCR4的小分子抑制剂的单一和联合治疗将在小鼠和人类肿瘤细胞和肿瘤模型中进行检验。这个项目的重点不是伯奇迈尔实验室多年来一直进行的基础研究，而是对基本发现的翻译研究和应用。因此，该项目将为在Schipper实验室和杜塞尔多夫的HNO诊所进行的临床试验做准备，最终目的是改善癌症患者的治疗。在医学上，这是极其重要的，因为目前针对头颈部癌症的靶向治疗的选择很少。计划进行以下实验。1.研究Met、Shp2、CXCR4等小分子抑制剂及其组合对体外培养的小鼠涎腺癌细胞增殖、分化及基因表达的影响。柏林集团，伯奇迈尔。2.选用Wnt、Mll1、Met、Shp2和CXCR4信号通路的抑制剂，在球体培养的人HNSCC细胞系中进行实验。施佩尔·杜塞尔多夫集团。3.将小鼠涎腺癌细胞移植到免疫缺陷小鼠体内后，将测试针对Wnt、Mll1、Met、Shp2和CXCR4的选定的抑制剂和组合。柏林集团，伯奇迈尔。4.从HPV阳性和HPV阴性的HNSCC患者中生长成球状的癌症干细胞样细胞将被检查对选定的抑制剂的反应。施佩尔·杜塞尔多夫集团。5.在细胞培养实验中已成功使用的抑制剂和抑制剂组合，将在小鼠身上测试从HNSCC患者获得的类似于人类癌症干细胞的移植细胞。柏林集团，伯奇迈尔。6.HPV阳性和HPV阴性的HNSCC细胞移植后，将确定治疗应答者和无应答者的基因表达特征。柏林和杜塞尔多夫，伯奇迈尔和施佩尔。

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.