OLIG2 Phosphorylation as a Drug Target for Glioma

OLIG2 磷酸化作为神经胶质瘤的药物靶点

• 批准号: 8672697
• 负责人: Charles D Stiles
• 金额: $ 43.2万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8672697
• 关键词: Address; Adjuvant; Adult; Age-Years; Antibodies; Astrocytoma; Brain Neoplasms; Cancer Etiology; Cause of Death; Cell Cycle; Cell Cycle Regulation; Cell Nucleus; Cells; Cessation of life; Clinical; Complement; Data; Diffuse; Drug Targeting; Epidermal Growth Factor Receptor; Gambling; Genetic; Genetic Engineering; Genetic Screening; Genomics; Glioma; Goals; Grant; Human; Learning; Libraries; MDM2 gene; Malignant - descriptor; Mediating; Modality; Monitor; Mus; Mutation; Organogenesis; Other Genetics; PTEN gene; Patients; Pharmaceutical Preparations; Phospho-Specific Antibodies; Phosphorylation; Phosphotransferases; Prognostic Marker; Progress Reports; Protein Kinase; Radiation; Radiation therapy; Resistance; Resolution; Risk; Sampling; Serine; Signal Transduction; Staging; Stem cells; TP53 gene; Testing; Tissue Banking; Tissue Banks; Tissue Sample; Tumor Subtype; Tumor Tissue; Woman; Work; attenuation; base; chemical genetics; clinical material; conventional therapy; drug development; expression vector; inhibitor/antagonist; kinase inhibitor; men; middle age; mimetics; mixed gliomas; mutant; neoplastic cell; nerve stem cell; neurogenesis; oligodendroglioma; p14ARF Protein; research study; response; skills; small hairpin RNA; small molecule; standard of care; stemness; success; therapeutic target; tissue repair; tool; transcription factor; tumor

DESCRIPTION (provided by applicant): A central function of p53 is to promote cell cycle exit and differentiation. Progenitor cells that drive organogenesis and tissue repair take a calculated risk to defeat p53 functions so as to sustain the replication competent state. Under auspices of this grant we have shown how neural progenitors occasionally lose this gamble. Our findings may have practical overtones for the treatment of high-grade glioma in humans. Put briefly we have learned: (1) That the bHLH transcription factor OLIG2 opposes p53 responses to genotoxic damage in both normal and malignant neural progenitors (2) that that the p53-supressive function of OLIG2 requires phosphorylation of an amino terminal triple serine motif and (3) that this triple serine motif of OLIG2 is phosphorylated in high-grade human gliomas. Our recent observations suggest that small molecule inhibitors of the OLIG2 protein kinase(s) could serve as targeted therapeutics for high-grade gliomas - either as stand alone modalities or (more likely) as adjuvants to radiotherapy and genotoxic drugs. The objectives of our study plan in this renewal application are to use human clinical materials to test this hypothesis (aims one and two) and to use genetically engineered murine neural progenitors to identify the critical OLIG2 kinase(s) (aim three). The PI and Co PI of this application have complementary backgrounds/skill sets and a tangible track record of productive interactions. The combined brain tumor tissue banking cores of Dana-Farber and UCSF can provide clinical sample sets that are statistically powered to address the issues raised in aims one and two. For aim three, we have devised robust, high throughput chemical and genetic screens for the OLIG2 protein kinase(s). These screens complement each other with respect to their strengths and weaknesses. Accordingly, we believe that odds of success are favorable.

描述（由申请人提供）：p53的核心功能是促进细胞周期退出和分化。驱动器官发生和组织修复的祖细胞会冒着一定的风险来破坏 p53 功能，以维持复制能力状态。在这笔资助的支持下，我们已经展示了神经祖细胞如何偶尔输掉这场赌博。我们的研究结果可能对人类高级别神经胶质瘤的治疗具有实际意义。简而言之，我们了解到：（1）bHLH 转录因子 OLIG2 对抗正常和恶性神经祖细胞中 p53 对基因毒性损伤的反应（2）OLIG2 的 p53 抑制功能需要氨基末端三丝氨酸基序的磷酸化；（3）OLIG2 的三丝氨酸基序在高级人类神经胶质瘤中被磷酸化。 我们最近的观察表明，OLIG2 蛋白激酶的小分子抑制剂可以作为高级别神经胶质瘤的靶向治疗药物 - 可以作为独立的治疗方法，也可以（更有可能）作为放射治疗和基因毒性药物的佐剂。我们在此更新申请中的研究计划的目标是使用人类临床材料来检验这一假设（目标一和二），并使用基因工程鼠神经祖细胞来鉴定关键的 OLIG2 激酶（目标三）。 该应用程序的 PI 和 Co PI 具有互补的背景/技能，以及富有成效的互动的切实记录。丹娜—法伯癌症研究所和加州大学旧金山分校联合脑肿瘤组织库核心可以提供临床样本集，这些样本集具有统计学意义，可以解决目标一和目标二中提出的问题。为了实现目标三，我们设计了针对 OLIG2 蛋白激酶的稳健、高通量化学和遗传筛选。这些屏幕各有优缺点，可以互相补充。因此，我们认为成功的可能性很大。