Stem Cell Therapies of Head and Neck Squamous Cell Carcinomas

头颈癌是一类异质性肿瘤，发生于口腔、口咽部、喉部、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（HNSCCs）。每年约有60万例新诊断患者，使HNSCC成为全球第五大最常见的恶性癌症。目前缺乏治疗HNSCC患者的方法。放疗、化疗和EGFR抗体治疗的效果有限，而且常常伴有损害性副作用。唾液腺鳞状细胞癌也很难治疗，因为它们的侵袭性和产生淋巴源性转移。在拟议的项目中，我们的目标是建立新的程序来干扰头颈部鳞状细胞癌的形成。这是一项双胞胎研究，涉及位于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Birchmeier实验室已经进行了多年的基础研究，而是基础发现的转化研究和应用。因此，该项目将为在Schipper实验室和杜塞尔多夫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方法。在医学上，这是极其重要的，因为目前头颈癌的靶向治疗选择很少。计划进行以下实验。1. 我们将研究Met、Shp2和CXCR4小分子抑制剂及其组合对小鼠唾液腺癌干细胞球培养中增殖、分化和基因表达的影响。柏林伯奇迈尔集团公司。选定的Wnt、Mll1、Met、Shp2和CXCR4信号抑制剂的作用将在球形培养的人类HNSCC细胞系中进行测试。2 .德国杜塞尔多夫集团。针对Wnt、Mll1、Met、Shp2和CXCR4的选定抑制剂和组合将在小鼠唾液腺癌干细胞移植到免疫缺陷小鼠后进行测试。柏林，伯奇迈尔集团。人类HPV阳性和HPV阴性HNSCC患者的肿瘤干细胞样细胞作为球体生长，将被检查对选定抑制剂的反应。5.德国杜塞尔多夫集团。已经在细胞培养实验中成功使用的抑制剂和抑制剂组合将在移植的人类癌症干细胞（如从HNSCC患者身上获得的细胞）上进行小鼠试验。柏林集团，伯奇迈尔。HPV阳性和HPV阴性HNSCC细胞的治疗应答和无应答的基因表达特征将在移植后确定。柏林和杜塞尔多夫，伯奇迈尔和席佩尔。

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.