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）：多形胶质母细胞瘤（GBM）几乎是致命的致命脑癌。 GBM的当前治疗方法是口服化学疗法的辐射。接受化学疗法和放射线治疗的GBM患者的预期寿命仅为14个月。这些统计数据很明显，需要更好的治疗方法来提高辐射对GBM的有效性。辐射会导致DNA损伤激活信号通路，这些信号通路被认为可以提高细胞修复DNA损伤的能力。在大多数情况下，由辐射触发的损伤传感途径取决于蛋白质磷酸化（将磷酸基团添加到蛋白质中）。蛋白质的磷酸化反映了两种相对的酶：激酶：将磷酸基团的磷酸基团和磷酸酶添加到从蛋白质中去除磷酸基团的磷酸盐。阻断激酶的药物已经成功地用于提高放射治疗的临床有效性。例如，除了阻断激酶的药物外，还需要辐射治疗晚期的头颈癌。但是，目前，蛋白质磷酸酶几乎没有引起关注，但有可能使辐射更有效。我们发现了称为磷酸酶6（PP6）的新发现的蛋白质磷酸酶的特定作用，该蛋白在调节称为DNA-PK的关键DNA修复蛋白中起着关键作用。 PP6的耗竭会显着使胶质母细胞瘤细胞敏感到辐射。我们的长期目标是通过使用阻断PP6激活DNA-PK的药物使胶质母细胞瘤细胞对辐射更敏感。但是，在使用此类药物之前，有必要定义辐射后PP6调节DNA-PK的分子机制。公共卫生相关性：尽管最佳治疗（放射线和口服化学疗法），但诊断为致命脑癌多形制服（GBM）的患者的寿命仅为14个月。该统计数据很明显，新颖的方法是提高GBM患者辐射有效性的必要性。我们的目标是开发一种药物，该药物将提高辐射对患者的有效性，从而改善GBM患者的预后。