OLIG2 Phosphorylation as a Drug Target for Glioma

描述（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一定的风险来破坏p53的功能，以维持复制能力。在这项资助下，我们展示了神经祖细胞是如何偶尔输掉这场赌博的。我们的发现可能对人类高级别胶质瘤的治疗具有实际意义。简而言之，我们已经了解到：(1)bHLH转录因子OLIG2在正常和恶性神经祖细胞中都反对p53对遗传毒性损伤的反应；(2)OLIG2的p53抑制功能需要一个氨基末端三丝氨酸基序的磷酸化；(3)OLIG2的这个三丝氨酸基序在高级别人类胶质瘤中被磷酸化。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胶质瘤的靶向治疗药物——无论是作为单独的治疗方式，还是（更有可能）作为放射治疗和基因毒性药物的佐剂。我们在这一更新申请中的研究计划的目标是使用人类临床材料来验证这一假设（目标一和目标二），并使用基因工程小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/技能集和有效交互的有形跟踪记录。丹娜-法伯和加州大学旧金山分校联合的脑肿瘤组织库核心可以提供临床样本集，这些样本集在统计学上能够解决目标一和目标二中提出的问题。对于第三个目标，我们已经为OLIG2蛋白激酶设计了强大的、高通量的化学和遗传筛选。这些屏幕在优势和劣势方面相互补充。因此，我们认为成功的可能性是有利的。

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.