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儿童星形细胞瘤（儿童最常见的脑癌）的护理标准。为此，我们将提高我们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利用了最近在约50%的儿童低级别星形细胞瘤中BRAF激活突变的观察结果，并解决了三个尚未解决的问题。William Hahn，MD/PhD和Jean Zhao，PhD将研究：（i）约50%的BRAF野生型肿瘤中的驱动突变是什么，（ii）与BRAF共发生的突变是什么，（iii）与BRAF共激活的其他细胞内激酶是什么？该项目的一个创新特点是最近开发了对甲醛固定、石蜡包埋样本进行基因图谱分析的方法。这些“石蜡友好”技术大大扩展了这些儿科肿瘤的可用样本。 项目2涉及bHLH转录因子Olig 2，重点是化学。Olig 2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无吸引力的靶标，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递送超过血/脑屏障。Charles Stiles博士和Loren Walensky医学博士/博士建议开发具有良好血/脑屏障渗透特性的Olig 2特异性抑制剂。该项目的创新特征是（i）“钉合肽”化学，以产生Olig 2拮抗剂，与（ii）MALDI质谱成像技术一起使用，以解决药物进入大脑间质区域的问题。 项目3解决了微环境在肿瘤生长中的作用。Rosalind Segal，MD/PhD开发了一种用于测试微环境对星形细胞瘤细胞的影响的新方法。在与神经外科医生Liliana Goumerova博士的合作中，她将使用来自不同脑区的儿科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”，以及肿瘤细胞龛是否促进肿瘤生长，存活和/或化学吸引。这些研究可能会导致新的策略，破坏星形细胞瘤细胞和他们的壁龛之间的接口。该项目的一个创新特点是考虑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，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。