Olig2 Antagonists for Targeted Therapy of Pediatric Astrocytomas

Olig2 拮抗剂用于儿童星形细胞瘤的靶向治疗

• 批准号: 8044509
• 负责人: Charles D Stiles
• 金额: $ 39.82万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-16 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044509
• 关键词: Adult; Adult Glioma; Agar; Area; Astrocytoma; BRAF gene; Biology; Blood; Blood - brain barrier anatomy; Brain; Cells; Central Nervous System Leukemia; Chemicals; Chemistry; Childhood; Childhood Astrocytic Tumor; Complex; DNA; Data; Disease; Funding Mechanisms; Generic Drugs; Goals; Human Resources; Image; Individual; Lead; Malignant neoplasm of central nervous system; Mass Spectrum Analysis; Methodology; Methods; Modification; Penetrance; Peptides; Protein Kinase; Proteins; Protocols documentation; Research; Research Personnel; Resolution; Series; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Surface; Technology; Therapeutic; Work; Xenograft Model; authority; developmental neurobiology; drug development; inhibitor/antagonist; innovation; interstitial; mimetics; neurodevelopment; neuropathology; notch protein; preclinical study; programs; research study; skills; small molecule; therapeutic target; tool; transcription factor; tumor; tumor xenograft

A broad body of data suggests that small molecule antagonists of the bHLH transcription factor Olig2 would have therapeutic value for both pediatric and adult astrocytomas. However transcription factors are generally considered to be unattractive targets for drug development because their interactions with DNA and with co-regulator proteins involve large and complex surface area contacts. A second major challenge - generic to any drug development project involving CNS cancers - is the blood/brain barrier. The broad goal of this project is to develop a small molecule Inhibitor of Olig2 that can cross the blood/brain barrier. Our two specific aims are to adapt a pair of innovative new methods towards this goal. Aim one is to use "stapled peptide" chemistry to generate small molecule alpha-helical mimetics that can disrupt the interaction between Olig2 and essential co-regulator proteins. Aim two is to use MALDI mass spectrometry imaging for direct imaging of these stapled peptide mimetics within the interstitial spaces ofthe brain at a resolution of 50 um (soon to be 10 um). Our study plan will merge these two methodologies into an iterative protocol for modification of lead compounds into potent, highly specific antagonists of Olig2 with good blood/brain barrier penetrance. The study plan will be carried out by a team with skill sets in three separate fields: The Stiles lab has credentials in the area of transcription factors and neural development. Co-investigator Loren Walensky is an authority on stapled peptide chemistry. Co-investigator Nathalie Agar provides the essential expertise in MALDI mass spectrometry imaging. The study plan for this project will benefit from economies of scale enabled by the Innovative Neuropathology Core. Mutually beneficial collaborative interactions with the investigators on Project One and Project Three will insure that the ultimate contributions of this program to the field of astrocytoma research exceeds the contributions ofthe individual project components.

大量的数据表明，bHLH转录因子Olig 2的小分子拮抗剂将 对儿童和成人星形细胞瘤均具有治疗价值。然而，转录因子是 通常被认为是药物开发的没有吸引力的靶点，因为它们与DNA的相互作用 并且与辅调节蛋白的接触涉及大而复杂的表面积接触。第二大挑战- 对于任何涉及CNS癌症的药物开发项目来说，通用的是血/脑屏障。广泛的目标 该项目的主要目的是开发一种能够穿过血/脑屏障的Olig 2小分子抑制剂。我们两 具体目标是为实现这一目标采用一对创新的新方法。 目的一是使用“钉合肽”化学来产生小分子α-螺旋模拟物， 可以破坏Olig 2和必需的辅助调节蛋白之间的相互作用。 目的二是利用MALDI质谱成像对这些钉合肽进行直接成像 模拟物在大脑间隙空间内的分辨率为50 μ m（很快将达到10 μ m）。 我们的研究计划将这两种方法合并为一个迭代方案，用于修改电极导线 化合物转化为具有良好血/脑屏障通透性的Olig 2的有效的、高度特异性的拮抗剂。的 研究计划将由一个在三个不同领域具有技能的团队执行： 在转录因子和神经发育领域的研究。共同调查员洛伦·瓦伦斯基是一位权威人士 关于钉合肽化学。共同研究者Nathalie Agar提供了MALDI质量的基本专业知识 光谱成像 本项目的研究计划将受益于创新的 神经病理学核心。与项目一的调查人员进行互利的合作互动 第三个项目将确保这个项目对星形细胞瘤领域的最终贡献 研究超过了单个项目的贡献。