Druggable Genetic Lesions in Pediatric Astrocytoma

儿童星形细胞瘤的可药物遗传病变

• 批准号: 8044508
• 负责人: William C. Hahn
• 金额: $ 38.15万
• 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/8044508
• 关键词: Academic Medical Centers; Address; Adult Glioma; Adverse effects; Astrocytoma; BRAF gene; Baltimore; Benign; Boston; Cancer Hospital; Chicago; Child; Childhood; Childhood Astrocytic Tumor; Childhood Brain Neoplasm; Clinical; Collection; Egypt; Event; Formaldehyde; Freezing; Gene Expression; Genes; Genetic; Genetic Screening; Genomics; Goals; Hospitals; Human; Instruction; Lesion; MDM2 gene; Medical center; Methods; Molecular Profiling; Mutate; Mutation; Nevus; New York; Oncogenic; Operative Surgical Procedures; Paraffin; Paraffin Embedding; Pathology; Pediatric Hospitals; Pediatric Neoplasm; Phosphotransferases; Protein Kinase; Protein-Serine-Threonine Kinases; Radiation therapy; Reagent; Recurrence; Relative (related person); Role; Sampling; Signal Transduction; Technology; Testing; Therapeutic; Tissues; Treatment Protocols; Tumor Suppressor Proteins; University Hospitals; Washington; chemotherapy; genome-wide; inhibitor/antagonist; innovation; loss of function; melanocyte; melanoma; mutant; nerve stem cell; neuro-oncology; new technology; resistance mechanism; senescence; small molecule; standard care; therapeutic target; translational study; tumor

We and others have recently found that activating mutations in the serine/threonine kinase BRAF may be found in as many as half of all pediatric low grade astrocytomas (LGA). The overarching goals of these studies are to characterize the role of mutant BRAF in these tumors and to identify other mutations that drive the formation of both low- and high-grade pediatric astrocytomas. Specifically, we propose to: Aim One: Use new "paraffin-friendly" genomic technologies to identify oncogenic mutations in pediatric astrocytomas. The ability to interrogate formaldehyde-fixed, paraffin-embedded archival tissues expands the available sample sets of these infrequent pediatric tumors by a factor of ten or more relative to fresh frozen tumor collections. We will use these technologies on a unique set of over 1000 archival tumor samples to address two important unresolved questions in the field. Specifically, (i) what are the recurrent mutations or amplifications in pediatric astrocytomas that lack BRAF mutations? and (ii) What are the mutations that co-occur with BRAF mutations? Aim Two: Use functional approaches to identify mutations that cooperate with activated BRAF in pediatric astrocytomas. Similarto what has been found in BRAF-mutant melanoma, we anticipate that other mutations cooperate with mutated BRAF in pediatric astrocytomas. We will use both candidate and unbiased approaches to identify such mutations through the transformation of neural progenitor cells. Aim Three: identify "druggable" signal generators that function upstream and downstream of BRAF n transformed neural progenitors. In the fullness of time, small molecule inhibitors of BRAF may be used for the treatment of BRAF mutant pediatric LGAs. However, multiple protein kinases have been shown to be co-activated in high-grade adult gliomas, and this is also likely to be the case in mutant BRAF-transformed pediatric astrocytomas. In this Aim, we will conduct kinome-wide genetic screens for kinases that can substitute for activated BRAF to dysregulate the proliferation of normal neural progenitor cells. This information will help define genes that may drive pediatric astrocytomas that lack BRAF mutations as well as defining potential mechanisms of resistance to the inhibition of BRAF. All three specific aims are supported by an Innovative Neuro Pathology Core and by shared technologies and reagents from Projects Two and Three. RELEVANCE (See instructions): Many pediatric brain tumors can be initially treated by surgery, chemotherapy and/or radiotherapy. However, the clinical side-effects ofthese treatments in growing children can be significant. Moreover, these tumors frequently recur and eventually fail to respond to standard treatment protocols. Thus, there is an urgent need for targeted therapeutics for these tumors. This project will identify and characterize promising targets that are ripe for translational studies to develop targeted therapeutics for children with pediatric brain tumors.

我们和其他人最近发现，丝氨酸/苏氨酸激酶BRAF中的激活突变可能是 在所有儿科低级星形胶质细胞（LGA）中，有多达一半的发现。这些的总体目标 研究是为了表征突变BRAF在这些肿瘤中的作用，并确定其他驱动的突变 低度和高级小儿星形胶质细胞瘤的形成。具体来说，我们建议： 目标一：使用新的“石蜡友好”基因组技术来鉴定致癌突变 小儿星形胶质细胞瘤。询问甲醛固定，石蜡包裹的档案组织的能力 将这些不经常的儿科肿瘤的可用样品集扩大了10倍或更多 新鲜的冷冻肿瘤收集。我们将在一组独特的1000多个档案肿瘤上使用这些技术 样本以解决该领域的两个重要的未解决问题。具体而言，（i）反复发生的是什么 缺乏BRAF突变的小儿星形细胞瘤的突变或扩增？ （ii）什么是 与BRAF突变共发生的突变？ 目标两个：使用功能方法来识别与激活的BRAF合作的突变 小儿星形胶质细胞瘤。 Similarto在Braf突变的黑色素瘤中发现了什么，我们预计 其他突变与小儿星形细胞瘤中的突变BRAF合作。我们将同时使用候选人和 通过神经祖细胞的转化来识别这种突变的无偏方法。 目标三：确定在BRAF上游和下游功能的“可吸毒”信号发生器 n转变的神经祖细胞。在时间的填充度中，可以使用BRAF的小分子抑制剂 用于治疗BRAF突变小儿LGA。但是，多种蛋白激酶已被证明是 在高级成人神经胶质瘤中共同激活，在突变体BRAF转换中也可能是这种情况 小儿星形胶质细胞瘤。在此目标中，我们将为激酶进行整个范围的遗传筛选 代替活化的BRAF来失调正常神经祖细胞的增殖。这 信息将有助于定义可能驱动缺乏BRAF突变以及 定义对抑制BRAF的抗性的潜在机制。 这三个特定目标均由创新的神经病理学核心支持，并由共享 第二和第三个项目的技术和试剂。 相关性（请参阅说明）： 许多小儿脑肿瘤最初可以通过手术，化学疗法和/或放射疗法进行治疗。然而， 这些在成长中的儿童治疗的临床副作用可能很重要。而且，这些肿瘤 经常复发，最终无法响应标准治疗方案。因此，迫切需要 用于这些肿瘤的靶向治疗剂。该项目将确定并表征有希望的目标 已经成熟了转化研究，以开发针对儿科脑肿瘤儿童的靶向治疗方法。