IR signaling through PP6, a potential molecular target for radiosensitization

通过 PP6 发出的红外信号，PP6 是放射增敏的潜在分子靶标

基本信息

批准号：
7992740
负责人：
James M Larner
金额：
$ 15.98万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7992740
关键词：
Affect Apoptosis Attention Attenuated Autophagocytosis Binding Cell Death Cell Extracts Cell Survival Cells Cessation of life Clinical effectiveness Complex DNA Damage DNA Double Strand Break DNA Repair DNA repair protein DNA-dependent protein kinase Diagnosis Dominant-Negative Mutation Double Strand Break Repair Drug usage Effectiveness Enzymes Equilibrium Exposure to Glioblastoma Goals Head and Neck Cancer In Vitro Interruption Ionizing radiation Lead Life Expectancy Malignant neoplasm of brain Mass Spectrum Analysis Mediating Methods Mitotic Modeling Modification Molecular Molecular Target Mutate Mutation Necrosis Nonhomologous DNA End Joining Oral Pathway interactions Patients Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Play Precipitation Protein Dephosphorylation Protein Kinase Protein phosphatase Proteins Radiation Radiation Tolerance Radiation therapy Radiation-Sensitizing Agents Radiosensitization Resistance Role SCAP2 gene Signal Pathway Signal Transduction Site Staging Synapses Testing Therapeutic Effect Time Toxic effect chemotherapy cytotoxic cytotoxicity design improved in vivo inhibitor/antagonist inorganic phosphate irradiation neoplastic cell novel novel strategies outcome forecast protein protein interaction public health relevance repaired response small hairpin RNA statistics tumor

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is an almost uniformly fatal brain cancer. The current treatment for GBM is radiation with oral chemotherapy. GBM patients treated with chemotherapy and radiation have life expectancies of only 14 months. These statistics make it obvious that better treatment approaches are needed to improve the effectiveness of radiation for GBM. Radiation causes DNA damage which activates signaling pathways that are thought to improve the ability of cells to repair DNA damage. The damage sensing pathways that are triggered by radiation, for the most part, are dependent on protein phosphorylation (adding a phosphate group to proteins). Protein phosphorylation reflects the balance between two opposing sets of enzymes: kinases that add a phosphate group to proteins and phosphatases that remove a phosphate group from proteins. Drugs that block kinases have already been successfully used to improve the clinical effectiveness of radiation therapy. For example, advanced-stage head and neck cancers are treated with radiation in addition to a drug that blocks kinases. At this time, however, protein phosphatases have received little attention but have the potential to make radiation more effective. We have discovered a specific role for a newly discovered protein phosphatase called phosphatase-6 (PP6) which plays a critical role in regulating a key DNA repair protein called DNA-PK. Depletion of PP6 dramatically sensitizes glioblastoma cells to radiation. Our long term goal is to make glioblastoma cells more sensitive to radiation through the use of drugs that block PP6's ability to activate DNA-PK. However, before such drugs can be used, it is necessary to define the molecular mechanisms by which PP6 regulates DNA-PK following radiation. PUBLIC HEALTH RELEVANCE: Despite optimal treatment (radiation and oral chemotherapy), patients diagnosed with the fatal brain cancer Glioblastoma multiforme (GBM) have life expectancies of only 14 months. This statistic makes it obvious that novel approaches are necessary to improve the effectiveness of radiation for GBM patients. Our goal is to develop a drug that will enhance the effectiveness of radiation for patients and thereby improve the prognosis of GBM patients.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是一种几乎都是致命的脑癌。目前 GBM 的治疗方法是放疗和口服化疗。接受化疗和放疗的 GBM 患者的预期寿命只有 14 个月。这些统计数据表明，需要更好的治疗方法来提高 GBM 放疗的有效性。辐射会导致 DNA 损伤，从而激活信号通路，从而提高细胞修复 DNA 损伤的能力。由辐射触发的损伤感知途径在很大程度上依赖于蛋白质磷酸化（向蛋白质添加磷酸基团）。蛋白质磷酸化反映了两组相反的酶之间的平衡：向蛋白质添加磷酸基团的激酶和从蛋白质中去除磷酸基团的磷酸酶。阻断激酶的药物已成功用于提高放射治疗的临床效果。例如，晚期头颈癌除了使用阻断激酶的药物外，还可以使用放射治疗。然而，目前蛋白磷酸酶还没有受到多少关注，但它有可能使放射治疗更加有效。我们发现了一种新发现的蛋白质磷酸酶的特殊作用，称为磷酸酶-6 (PP6)，它在调节称为 DNA-PK 的关键 DNA 修复蛋白方面发挥着关键作用。 PP6 的消耗使胶质母细胞瘤细胞对辐射显着敏感。我们的长期目标是通过使用阻断 PP6 激活 DNA-PK 能力的药物，使胶质母细胞瘤细胞对辐射更加敏感。然而，在使用此类药物之前，有必要明确 PP6 在辐射后调节 DNA-PK 的分子机制。公共卫生相关性：尽管采用了最佳治疗（放射和口服化疗），但诊断出患有致命性脑癌多形性胶质母细胞瘤 (GBM) 的患者的预期寿命仅为 14 个月。这一统计数据清楚地表明，需要新的方法来提高 GBM 患者的放疗效果。我们的目标是开发一种药物，增强患者放疗的有效性，从而改善 GBM 患者的预后。