BRAIN TUMOR SPORT GRANT

项目摘要(见说明)：这一修订后的孢子更新申请代表了加州大学旧金山分校海伦·迪勒家庭综合癌症中心神经肿瘤学项目的跨学科研究团队的努力，以将他们的专业知识应用于专注于脑癌的转译研究。该提案有四个总体具体目标：1)确定有助于脑癌存活的可能性的因素；2)确定预测低级别胶质瘤患者复发和预后的成像参数和相关组织生物标志物；3)为含有BRAF突变的儿童脑瘤开发改进的治疗方法；以及4)改进脑癌的免疫治疗。该提案的核心是四个翻译研究项目。项目1将确定与低级别胶质瘤和GBM患者生存相关的遗传变异，并将在全基因组研究中确定的生存基因与IDH突变和其他分子特征相结合，这是迄今为止与胶质瘤生存相关的综合基因组学的最佳范例。项目2将评估在之前的资助期中确定的光谱标记物预测低级别胶质瘤患者进展时间和总存活率的能力。该项目还包括首次对驱动低级别胶质瘤形成和进展的突变进行分析，这可能有助于将基因变化与光谱变化联系起来。项目3是这项提议的新内容，将建立在确认儿童脑瘤中BRAF突变的开创性研究基础上。该项目将对基于机制的BRAF、MEK和细胞周期蛋白依赖性激酶抑制剂的新组合进行临床前评估，并在儿童脑瘤人群中启动BRAF抑制剂的首次临床试验。项目4将确定PI(3)Ky/B7-H1通路对免疫调节性T细胞和巨噬细胞扩张的影响，并将在一项针对GBM患者的临床试验中探讨抑制PI(3)K/B7-H1在加强免疫治疗方面的作用。该孢子提案还要求支持职业发展和发展研究方案，以及支持这四个项目努力的四个核心(行政、生物医学/病理学、动物、生物统计学和临床)。

PROJECT SUMMARY (See instructions): This revised SPORE renewal application represents the efforts of interdisciplinary teams of investigators from the Neuro-Oncology Program ofthe UCSF Helen Diller Family Comprehensive Cancer Center to apply their expertise to translational research focused on brain cancer. The proposal has four overall specific objectives: 1) to identify factors that contribute to the likelihood of surviving brain cancer; 2) to identify Imaging parameters and linked tissue biomarkers that predict recurrence and outcome in patients with low grade glioma; 3) to develop improved therapies for pediatric brain tumors harboring BRAF mutations; and 4) to improve immunotherapy for brain cancer. At the heart of the proposal are four translational research projects. Project 1 will identify genetic variations associated with survival in low-grade glioma and GBM patients, and will integrate survival genes identified in genome-wide association studies with IDH mutation and other molecular characteristics in the best example of integrative genomics pertaining to glioma survival to date. Project 2 will assess the ability of the spectroscopic markers identified in the previous funding period to predict time to progression and overall survival in low-grade glioma patients. The project also includes a first-ever analysis of the mutations that drive low-grade glioma formation and progression and which may help link genetic alterations to the spectroscopic changes noted. Project 3 is new to this proposal and will build on seminal studies that identified BRAF mutations in pediatric brain tumors. The project will preclinically evaluate new combinations of mechanism-based BRAF, MEK, and cyclin-dependent kinase inhibitors as well as initiate the first clinical trials of BRAF inhibitors in the pediatric brain tumor population. Project 4 will determine the impact of the PI(3)Ky/B7-H1 pathway on expansion of immunomodulatory T-cells and macrophages, and will investigate the utility of inhibiting PI(3)K/B7-H1 to augment immunotherapy in a clinical trial for GBM patients. This SPORE proposal also requests support for the Career Development and Developmental Research Programs, and four Cores (Administrative, Biospecimen/Pathology, Animal, and Biostatistics and Clinical) that will support the efforts of the four projects.