Advancing Treatments for Pediatric Craniopharyngioma (ATPC): Preliminary Assessment of the Cyst Fluid Inflammatory Milieu

项目摘要 这项小型研究资助的主要研究者是一名儿科神经外科医生，他对以下方面特别感兴趣： 改善神经和功能结果（例如生活质量、学校表现、日常活动） 生活）的儿童患有造釉细胞瘤性颅咽管瘤（ACP）。这在神经学上 毁灭性的肿瘤，由于其低死亡率，迫使儿童和他们的家庭面临终身的慢性 和严重的残疾作为一名初级调查员，PI开发并领导了北美唯一的 致力于儿科ACP研究的联盟，儿科颅咽管瘤的先进治疗 （ATPC）。这个奖项的目的是确定是否试点数据，汉金森博士来自ACP 标本值得进一步研究与动物模型，并可能人体试验。分析细胞因子 ACP囊肿液的表达表明，与另一个囊肿相比， 形成小儿脑瘤毛细胞星形细胞瘤这就增加了FDA批准的药物 特异性靶向IL-6/IL-6受体（促炎途径的关键介质）的药物可以控制ACP 囊肿生长这可能为患有ACP的儿童揭示一种新的治疗选择，无论是通过改善肿瘤 控制或促进更安全的治疗手术。通过利用科罗拉多大学NIH支持的 跨学科研究中心，这个小项目将确定ACP的细胞成分是负责 促炎细胞因子的分泌，以及IL-6/IL-6 R阻断是否减轻了这一过程。 博士汉金森在一个非常适合完成这项工作的环境中工作。他和一个叫 博士尼古拉斯·福尔曼是他KL 2职业发展奖的主要导师之一。Foreman医生 是一个成熟的高级研究员和领导者的研究有关免疫生物学的小儿脑 肿瘤，尤其是室管膜瘤。Hankinson博士还接受了生物信息学方面的正式培训， 他的KL 2奖期间，这导致了与Aik-Choon Tan博士，主任， 科罗拉多癌症大学转化生物信息学和癌症系统生物学实验室 中心因此，本项目的主要人员在所需的所有方法方面都具有相当的专业知识 成功地完成了这个奖项。这些包括流式细胞术、RNAseq、细胞增殖测定 和细胞因子微阵列分析。汉金森博士还与以下机构建立了合作关系： ACP研究的国际领导者。与本奖项最相关的是胡安·佩德罗博士 Martinez-Barbera建立了ACP唯一的动物模型。如果这项工作的结果是有希望的， 我们将与马丁内斯-巴贝拉博士合作进行动物研究。如果结果不表明 鉴于ACP治疗的巨大进步潜力，我们将继续将资源集中在 我们最近发表的关于ACP基因表达的研究路线。

Project Summary The principal investigator for this Small Research Grant is a pediatric neurosurgeon with specific interest in improving the neurological and functional outcomes (e.g. quality of life, school performance, activities of daily living) for children who are afflicted with adamantinomatous craniopharyngioma (ACP). This neurologically devastating tumor, due to its low mortality rate, forces children and their families to face a lifetime of chronic and profound disability. As a junior investigator, the PI has developed, and leads, North America's only consortium dedicated to the study of pediatric ACP, Advancing Treatment for Pediatric Craniopharyngioma (ATPC). The goal of this award is to determine whether pilot data that Dr. Hankinson derived from ACP specimens merits further investigation with animal models, and potentially human trials. Analysis of cytokine expression from ACP cyst fluid indicated a unique proinflammatory profile, when compared to another cyst- forming pediatric brain tumor, Pilocytic Astrocytoma. This raises the possibility that FDA approved medications that specifically target IL-6/IL-6 receptor, a critical mediator of the proinflammatory pathway, could control ACP cyst growth. This could reveal a novel therapeutic option for children with ACP, either through improved tumor control or by facilitating safer curative surgery. By leveraging the University of Colorado's NIH-supported interdisciplinary research centers, this small project will identify which cellular component of ACP is responsible for the secretion of proinflammatory cytokines and, further, if IL-6/IL-6R blockade mitigates this process. Dr. Hankinson works in an environment that is ideal for the completion of this work. He works very closely with Dr. Nicholas Foreman, who is one of the primary mentors on his KL2 career development award. Dr. Foreman is a well-established senior investigator and leader in research regarding the immunobiology of pediatric brain tumors, most notably ependymoma. Dr. Hankinson has also undertaken formal training in bioinformatics during his KL2 award period, which resulted in a strong relationship with Dr. Aik-Choon Tan, Director of the Translational Bioinformatics and Cancer Systems Biology Laboratory at the University of Colorado Cancer Center. As such, the key personnel of this project possess considerable expertise in all the methods required for the successful completion of this award. These include flow cytometry, RNAseq, cell proliferation assays and cytokine microarray analysis. Dr. Hankinson has additionally built collaborative relationships with international leaders in ACP research. Most relevant to this award proposal is that with Dr. Juan Pedro Martinez-Barbera, who has established the only animal models of ACP. If the results of this work are promising, we will proceed to animal studies through collaboration with Dr. Martinez-Barbera. If the results do not indicate the potential for considerable advancement in the therapy for ACP, we will continue to focus our resources on the lines of research that were defined in our recent publication regarding ACP gene expression.