Therapeutic Opportunities for Pediatric Astrocytoma

该计划的长期目标是提高儿童星形细胞瘤的护理标准--最 儿童常见的脑癌。为此，我们将提高对星形细胞瘤的认识 生物学，并为这些肿瘤开发新的诊断、预后和治疗工具。的重要意义。 这项工作是，中枢神经系统的原发性癌症现在已经超过白血病，成为最主要的癌症 儿童癌症相关死亡的原因。 项目1利用了最近观察到的在~50%的儿童低血压病患者中激活BRAF突变的情况 对星形细胞瘤进行分级，并解决三个未解决的问题。William Hahn，医学博士和Jean 赵博士将研究：(I)BRAF野生型~50%的肿瘤的驱动突变是什么，(Ii)是什么 是与BRAF共同发生的突变，以及(Iii)其他哪些细胞内激酶与之共同激活 布拉夫？该项目的一个创新特征是最近开发的遗传图谱方法 甲醛固定、石蜡包埋的样品。这些“石蜡友好”技术极大地扩展了 这些儿科肿瘤的现有样本。 项目2涉及bHLH转录因子寡核苷酸， 集中在化学物质上。OLIG2是儿童星形细胞瘤靶向治疗的有力候选者。然而， 转录因子通常被认为是药物开发的不具吸引力的靶点，因为它们 与DNA的相互作用涉及到大而复杂的表面积接触。大脑中的另一个一般性问题 肿瘤药物的开发正在确保超越血/脑屏障的输送。查尔斯·斯泰尔斯，博士和罗伦 Walensky，MD/PhD建议开发具有良好的穿透性的Opol2的特异性抑制剂 血/脑屏障。该项目的创新特点是：(一)用化学装订的方法合成寡聚体2 与(Ii)MALDI质谱学成像技术一起使用的拮抗剂以解决药物渗透到 大脑的间质区域。 项目3解决了微环境在肿瘤生长中的作用。 罗莎琳德·西格尔，医学博士/博士，开发了一种新的测试方法，用于测试微环境对 星形细胞瘤细胞。与神经外科医生Liliana Goumerova合作，她将使用来自 儿童星形细胞瘤源自不同脑区以确定肿瘤细胞是否对 它们起源的位置，以及肿瘤细胞是否促进肿瘤的生长、存活和/或 化学吸引力。这些研究可能导致新的策略来破坏星形细胞瘤之间的接口 细胞和它们的壁龛。该项目的一个创新特点是考虑将纤毛作为信号细胞器。 协调对微环境的反应。这三个项目相互作用，它们是 由创新的神经病理学(INP)核心实现的规模经济进一步统一。

The long-term goal of this program is to improve the standard of care for pediatric astrocytomas - the most common brain cancers in children. Towards this end, we will improve our understanding of astrocytoma biology and develop new diagnostic, prognostic and therapeutic tools for these tumors. The significance of the work is that primary cancers of the central nervous system have now surpassed leukemia as the leading cause of cancer-related death in children. Project 1 draws upon recent observations of activating mutations in BRAF in ~50% of pediatric low grade astrocytomas and addresses three unresolved questions. William Hahn, MD/PhD and Jean Zhao, PhD will study: (i) what are the driving mutations in the ~50% of tumors wild type for BRAF, (ii) what are the mutations that co-occur with BRAF and (iii) what other intracellular kinases are co-activated with BRAF? An innovative feature of this project is recently developed methods for genetic profiling of formaldehyde-fixed, paraffin-embedded samples. These "paraffin-friendly" technologies greatly expand the available samples of these pediatric tumors. Project 2 addresses the bHLH transcription factor Olig2, with a chemical focus. Olig2 is a strong candidate for targeted therapy of pediatric astrocytomas. However, transcription factors are generally considered to be unattractive targets for drug development because their interactions with DNA involve large and complex surface area contacts. Another generic problem in brain tumor drug development is ensuring delivery beyond the blood/brain barrier. Charles Stiles, PhD and Loren Walensky, MD/PhD propose to develop specific inhibitors of Olig2 with good penetrance properties for the blood/brain barrier. Innovative features of this project are (i) "stapled peptide" chemistry to create Olig2 antagonists used with (ii) MALDI mass spectrometry imaging technology to address drug penetrance into the interstitial areas of the brain. Project 3 addresses the role of microenvironment in tumor growth. Rosalind Segal, MD/PhD has developed a novel assay for testing the effects of microenvironments on astrocytoma cells. In collaboration with neurosurgeon Liliana Goumerova, MD, she will use tumor cells from pediatric astrocytomas derived from different brain regions to determine whether tumor cells are "addicted" to the location where they originated, and whether tumor cell niches promote tumor growth, survival, and/or chemoattraction. These studies may lead to new strategies for disrupting the interface between astrocytoma cells and their niches. An innovative feature of this project is a consideration of cilia as signaling organelles that coordinate responses to the microenvironment. The three projects interact with one another and are further unified by economies of scale enabled by an Innovative Neuropathology (INP) core.