New Cancer Therapeutic Target

描述（由申请人提供）：胶质母细胞瘤（GBM）患者的中位生存期为12-15个月。延长这种疾病患者的生命是一个未得到满足的关键需求。显然，需要更有效的治疗方法，确定新的靶点是加速实现这一目标的关键战略。该应用基于我们对GBM的新候选激酶靶点STK 17 A的独特发现。STK 17 A是丝氨酸/苏氨酸蛋白激酶DAP家族的新成员。我们的初步数据直接将STK 17 A与GBM患者的生存联系起来。STK 17 A在GBM中高度过表达。STK 17 A过表达和拷贝数增加与胶质瘤患者的显著生存劣势相关。在建立的和原代人GBM中STK 17 A的敲低导致增殖减少和对营养应激敏感的细胞。STK 17 A的敲低与ULK 1的显著降低相关，ULK 1是自噬的关键限速组分，并且STK 17 A敲低抑制响应于细胞毒性和营养应激的自噬。STK 17 A的小分子量抑制剂也抑制GBM细胞的生长/存活。STK 17 A是我们实验室发现的一个全新的GBM候选激酶靶点。该项目的广泛，长期目标是确定STK 17 A在促进GBM增殖和存活中的作用，并发现靶向STK 17 A是否是一种有前途的策略，以对抗对当前形式的治疗具有抗性的GBM。我们的假设是STK 17 A是GBM中令人兴奋的新治疗靶点和预后生物标志物，并且STK 17 A的过表达促进GBM的进展和生长，并在营养剥夺和治疗诱导的遗传毒性应激后促进自噬介导的肿瘤细胞存活。使用临床样品以及体外和体内模型的转化研究将 机械地检验我们的假设这种应用是创新的，因为它是基于我们实验室对一种新的丝氨酸/苏氨酸激酶产生的新数据，这种激酶以前没有与癌症或肿瘤细胞的化学敏感性相关。提出的目标是重要的，因为它们有可能将该领域引入一个全新的GBM靶点，这可能导致GBM和其他癌症的新疗法的开发，并提供一种新的策略来使癌症对现有疗法敏感。该项目还将导致支持靶向自噬作为对抗癌症的一般策略的发现，并提供在GBM中这样做的目标。通过现有的独特资源和专家合作者，我们准备为我们理解STK 17 A作为GBM的预后标志物和治疗靶点做出重大贡献。

DESCRIPTION (provided by applicant): The median survival of patients with glioblastoma (GBM) is 12-15 months. Extending the life of individuals with this disease is a critical unmet need. Clearly more effective therapies are needed and the identification of new targets is a key strategy to accelerate progress towards this goal. This application is based on our unique discovery of a new candidate kinase target for GBM called STK17A. STK17A is a novel member of the DAP family of serine/threonine protein kinases. Our preliminary data directly links STK17A to survival of GBM patients. STK17A is highly overexpressed in GBM. STK17A overexpression and increased copy number is associated with a significant survival disadvantage for patients with glioma. Knockdown of STK17A in established and primary human GBM results in a decrease in proliferation and sensitized cells to nutritional stress. Knockdown of STK17A is associated with a marked decrease in ULK1, a critical rate-limiting component of autophagy and STK17A knockdown represses autophagy in response to cytotoxic and nutritional stress. Small molecular weight inhibitors of STK17A also inhibit the growth/survival of GBM cells. STK17A is an entirely new candidate kinase target for GBM that our lab has uncovered. The broad, long-term goal of this project is to determine the role of STK17A in promoting GBM proliferation and survival and to discover whether targeting STK17A is a promising strategy to combat GBM which is resistant to current forms of therapy. Our hypothesis is that STK17A is an exciting and new therapeutic target and prognostic biomarker in GBM and that overexpression of STK17A promotes progression and growth of GBM and promotes autophagy-mediated tumor cell survival upon nutrient deprivation and therapy-induced genotoxic stress. Translational studies using clinical samples and in vitro and in vivo models will mechanistically test our hypothesis. This application is innovative since it is based on new data generated by our laboratory on a novel serine/threonine kinase that has not previously been linked to cancer or tumor cell chemosensitivity. The proposed aims are significant since they have the potential to introduce the field to an entirely new GBM target that could lead to development of new therapies for GBM and other cancers and provide a new strategy to sensitize cancers to existing therapies. This project will also lead to findings to support targetig autophagy as a general strategy to combat cancer and provides a target in which to do so in GBM. Through the unique resources available and expert collaborators we are poised to make significant contributions to our understanding of STK17A as a prognostic marker and therapeutic target for GBM.