New Cancer Therapeutic Target

新的癌症治疗靶点

• 批准号: 8751023
• 负责人: MICHAEL J SPINELLA
• 金额: $ 17.62万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8751023
• 关键词: Autophagocytosis; BRAF gene; Brain Neoplasms; Cell Cycle Arrest; Cell Line; Cell Survival; Cells; Clinical; Clinical Research; Collaborations; Data; Databases; Development; Disadvantaged; Disease; Drug usage; ERBB2 gene; Epidermal Growth Factor Receptor; Family; Gene Targeting; Genotoxic Stress; Glioblastoma; Glioma; Goals; Gray unit of radiation dose; Growth; Head; Health; Homologous Gene; Human; Hypoxia; In Vitro; Individual; Israel; Laboratories; Lead; Life; Link; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Mediating; Metabolism; Molecular Weight; Mutate; Mutation; Norris Cotton Cancer Center; Nutrient; Nutritional; Oncologist; Outcome; Pathologist; Pathway interactions; Patients; Phosphotransferases; Preclinical Drug Evaluation; Prevalence; Prognostic Marker; Protein Kinase; Protein-Serine-Threonine Kinases; RNA Interference; Regulation; Research; Resistance; Resources; Rewards; Role; Sampling; Serum; Signal Pathway; Starvation; Stress; Testing; Tissue Microarray; Translational Research; Tumorigenicity; Work; Xenograft procedure; base; brain tissue; cancer cell; chemotherapy; combat; cytotoxic; deprivation; effective therapy; high risk; in vivo Model; inhibitor/antagonist; innovation; kinase inhibitor; malignant breast neoplasm; medical schools; melanoma; member; migration; neoplastic cell; new therapeutic target; novel; novel therapeutics; overexpression; research study; response; therapeutic target; tool; translational study; tumor; tumor progression

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.

描述(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。延长患有这种疾病的人的生命是一个关键的未得到满足的需求。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。这一应用是基于我们对GBM的一个新的候选激酶靶标STK17A的独特发现。STK17A是DAP丝氨酸/苏氨酸蛋白激酶家族的新成员。我们的初步数据直接将STK17A与GBM患者的生存联系起来。STK17A在GBM中高表达。STK17A的过度表达和拷贝数的增加与胶质瘤患者的生存劣势有关。STK17A在已建立的和原代人类GBM中被敲除，导致细胞增殖减少，并使细胞对营养应激敏感。STK17A的敲除与ULK1的显著减少有关，ULK1是自噬的关键限速成分，STK17A敲除抑制自噬以响应细胞毒性和营养压力。小分子量的STK17A抑制剂也能抑制GBM细胞的生长/存活。STK17A是我们实验室发现的一种全新的GBM候选激酶靶点。该项目的广泛、长期目标是确定STK17A在促进GBM增殖和存活方面的作用，并发现靶向STK17A是否是对抗对当前治疗形式耐药的GBM的一种有前景的策略。我们的假设是，STK17A是一个令人兴奋的新的治疗靶点和预后生物标志物，在营养剥夺和治疗诱导的基因毒性应激下，STK17A的过表达促进了GBM的进展和生长，并促进了自噬介导的肿瘤细胞的存活。使用临床样本以及体外和体内模型的翻译研究将 机械地检验我们的假设。这一应用是创新的，因为它是基于我们实验室产生的关于一种新的丝氨酸/苏氨酸激酶的新数据，该数据以前没有与癌症或肿瘤细胞的化疗敏感性有关。拟议的目标具有重要意义，因为它们有可能为该领域引入一种全新的GBM目标，这可能导致开发针对GBM和其他癌症的新疗法，并提供一种新的战略，使癌症对现有疗法敏感。该项目还将导致支持将目标自噬作为抗击癌症的一般战略的结果，并提供在GBM中这样做的目标。通过独特的可用资源和专家合作者，我们准备为我们理解STK17A作为GBM的预后标志和治疗靶点做出重大贡献。