Therapeutic Opportunities for Pediatric Astrocytoma

儿童星形细胞瘤的治疗机会

• 批准号: 8019642
• 负责人: ROSALIND A. SEGAL
• 金额: $ 166.01万
• 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/8019642
• 关键词: Therapeutic; Opportunities; Pediatric; Astrocytoma

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 chemoattractipn. 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.

该计划的长期目标是提高小儿星形细胞瘤（儿童最常见的脑癌）的护理标准。为此，我们将提高对星形细胞瘤生物学的理解，并为这些肿瘤开发新的诊断、预后和治疗工具。这项工作的意义在于，中枢神经系统的原发性癌症现已超过白血病，成为儿童癌症相关死亡的主要原因。 项目 1 利用最近对约 50% 儿童低级别星形细胞瘤中 BRAF 激活突变的观察结果，并解决了三个未解决的问题。 William Hahn 医学博士/哲学博士和 Jean Zhu 博士将研究：(i) 大约 50% 的野生型肿瘤中 BRAF 的驱动突变是什么，(ii) 与 BRAF 共同发生的突变是什么，以及 (iii) ) 还有哪些其他细胞内激酶与 BRAF 共同激活？该项目的一个创新特点是最近开发的甲醛固定、石蜡包埋样品的基因分析方法。这些“石蜡友好”技术极大地扩展了这些儿科肿瘤的可用样本。 项目 2 以化学为重点，研究 bHLH 转录因子 Olig2。 Olig2 是小儿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中没有吸引力的靶标，因为它们与 DNA 的相互作用涉及大而复杂的表面积接触。脑肿瘤药物开发中的另一个普遍问题是确保药物递送超越血/脑屏障。 Charles Stiles 博士和 Loren Walensky 医学博士/博士提议开发对血/脑屏障具有良好渗透性的 Olig2 特异性抑制剂。该项目的创新特点是 (i) “钉合肽”化学来创建 Olig2 拮抗剂，与 (ii) MALDI 质谱成像技术一起使用，以解决药物渗透到大脑间质区域的问题。 项目 3 探讨微环境在肿瘤生长中的作用。 Rosalind Segal 医学博士/博士开发了一种新的检测方法，用于测试微环境对星形细胞瘤细胞的影响。她将与神经外科医生 Liliana Goumerova 医学博士合作，利用来自不同大脑区域的小儿星形细胞瘤的肿瘤细胞来确定肿瘤细胞是否对它们起源的位置“上瘾”，以及肿瘤细胞生态位是否促进肿瘤生长、存活和生存。 /或化学吸引。这些研究可能会带来破坏星形细胞瘤细胞与其生态位之间界面的新策略。该项目的一个创新特点是将纤毛视为协调对微环境的反应的信号细胞器。这三个项目相互影响，并通过创新神经病理学 (INP) 核心实现的规模经济进一步统一。