SPORE: Brain Tumore SPORE Grant

描述（由申请人提供）：此修订后的SPORE更新申请代表了UCSF Helen Diller家庭综合癌症中心神经肿瘤学项目的跨学科研究人员团队的努力，将其专业知识应用于脑癌的转化研究。该提案有四个总体具体目标：1）确定有助于脑癌存活可能性的因素; 2）确定预测低级别胶质瘤患者复发和结局的成像参数和相关组织生物标志物; 3）开发针对携带BRAF突变的儿科脑肿瘤的改进疗法;以及4）改善脑癌的免疫疗法。该提案的核心是四个转化研究项目。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，并将整合全基因组关联研究中确定的生存基因与IDH突变和其他分子特征，这是迄今为止与胶质瘤生存相关的整合基因组学的最佳范例。项目2将评估前一个资助期确定的光谱标记物预测低级别胶质瘤患者进展时间和总生存期的能力。该项目还包括对驱动低级别胶质瘤形成和进展的突变的首次分析，这可能有助于将遗传改变与所指出的光谱变化联系起来。项目3是该提案的新内容，将建立在确定儿科脑肿瘤中BRAF突变的开创性研究基础上。该项目将在临床前评估基于机制的BRAF、MEK和细胞周期蛋白依赖性激酶抑制剂的新组合，并在儿科脑肿瘤人群中启动BRAF抑制剂的首次临床试验。项目4将确定PI（3）K//B7-H1通路对免疫调节性T细胞和巨噬细胞扩增的影响，并将研究抑制PI（3）K/B7-H1以在GBM患者的临床试验中增强免疫治疗的效用。该SPORE提案还要求支持职业发展和发展研究计划，以及支持四个项目工作的四个核心（行政，生物标本/病理学，动物，生物统计学和临床）。

DESCRIPTION (provided by applicant): This revised SPORE renewal application represents the efforts of interdisciplinary teams of investigators from the Neuro-Oncology Program of the 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) o 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)K//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.