Brain Tumor SPORE Grant

项目总结/摘要 此SPORE更新申请代表了跨学科研究团队的努力 来自UCSF Helen Diller家庭综合癌症中心的神经肿瘤学项目 （HDFCCC）将他们的知识和专业知识应用于专注于脑癌的转化研究。 该SPORE提案有三个总体具体目标：1）确定有助于 脑癌存活的可能性; 2）确定可以帮助预测的非侵入性成像参数 神经胶质瘤患者的治疗反应; 3）开发更好的基于机制的治疗方法， 脑癌的治疗该提案的核心是四个新的转化研究项目， 每一个都是由应用和基础研究人员组成的团队驱动的，每一个都旨在创造新的工具， 用于诊断和治疗脑肿瘤的治疗方式。项目1是一项新的研究 受先前SPORE资助的成功鉴定分子特征（TERT启动子）的激励， 突变，1p/19q缺失和IDH1突变），将低级别胶质瘤分为4个不同的组， 沿着其他人的工作，导致WHO神经胶质瘤分类标准的修改。项目1 研究人员现在假设，分析各种循环髓样细胞的水平，而不是 肿瘤分子特征，可能会产生进展，在分化预后IDH野生型 胶质母细胞瘤后占一定的临床特点。他们将使用一个 他们开创的方法，定义和定量来自新鲜或 基于免疫细胞基因组中DNA甲基化模式的冷冻外周血，一个新的领域 免疫甲基组学的研究。项目2是一项新的研究，部分由以前的孢子促进- 资助的研究使用MRSI非侵入性地定义代谢物稳态水平的变化 与低级别胶质瘤进展相关的疾病在项目2中，研究人员假设， 加州大学旧金山分校开发的超极化碳13（C13）成像可以提供补充信息 关于代谢过程，这反过来又可以用来非侵入性地区分正常 在人类胶质母细胞瘤背景下的脑、肿瘤和胶质增生。项目3是一项新的研究， 科斯特洛实验室的开创性工作，确定GABP作为转录因子， 结合突变的TERT启动子并驱动TERT表达、细胞永生化和 包括神经胶质瘤在内的多种癌症的肿瘤发生。项目3中提出的工作将奠定 为开发基于突变型TERT启动子的治疗方法奠定了基础， 在人脑胶质瘤样本中，通过直接定义 GABP在TERT激活中的作用，以及通过设计方法来增加TERT沉默后的细胞死亡。 项目4是一个新的项目，其基础是观察到下游mTOR靶点的抑制 4EBP对于PI3K驱动的胶质母细胞瘤的有效生长抑制是至关重要的，并且4EBP的临床失败可能是由于4EBP的临床失败。 胶质母细胞瘤中的PI3K通路靶向治疗是持续4EBP不足的结果 镇压因此，项目4的研究人员合成了一类全新的分子， 在体内提供持续的4EBP抑制和生长抑制，在本项目中将定义 药物的最佳神经胶质瘤靶向人群，将优化先导药物的疗效，并提出 这是第一次在神经胶质瘤患者中进行这类新药物的临床试验。这份SPORE提案还要求 继续支持极其重要的职业提升和发展研究 程序和三个核心（管理、生物标本/病理学以及生物统计学和临床） 这将支持四个项目的努力。通过处理所述总体具体目标， 在这项脑肿瘤孢子应用中提出的研究很有可能改变 我们检测、诊断和治疗脑癌的方式。

Project Summary/Abstract This 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 (HDFCCC) to apply their knowledge and expertise to translational research focused on brain cancer. This SPORE proposal has three overall specific objectives: 1) to identify factors that contribute to the likelihood of surviving brain cancer; 2) to identify noninvasive imaging parameters that can help predict therapeutic response in patients with glioma; and 3) to develop better mechanism-based therapies for the treatment of brain cancer. The heart of the proposal is four new translational research projects, each driven by teams of applied and basic investigators, and each intended to create novel tools and therapeutic modalities useful in the diagnosis and treatment of brain tumors. Project 1 is a new study motivated by previous SPORE-funded successes in identifying molecular features (TERT promoter mutation, 1p/19q deletion, and IDH1 mutation) that divide lower grade glioma into 4 distinct groups, and along with work from others, led to modifications in WHO criteria for glioma classification. Project 1 investigators now hypothesize that an analysis of levels of various circulating myeloid cells, rather than of tumor molecular features, may yield advances in differentiating prognosis for IDH-wildtype glioblastoma after accounting for certain clinical characteristics. They will test this hypothesis using an approach they pioneered that defines and quantitates aberrant immune cell populations from fresh or frozen peripheral blood based on patterns of DNA methylation in the immune cell genomes, a new field of study called immunomethylomics. Project 2 is a new study facilitated in part by previous SPORE- funded studies that used MRSI to noninvasively define changes in steady state levels of metabolites that related to low-grade glioma progression. In Project 2 the investigators hypothesize that the use of hyperpolarized carbon-13 (C13) imaging, developed at UCSF, can provide complementary information about metabolic processes, which in turn can be used to noninvasively differentiate between normal brain, tumor and gliosis in the human glioblastoma setting. Project 3 is a new study that evolved from groundbreaking work from the Costello lab that identified GABP as the transcription factor that uniquely binds the mutant TERT promoter and drives TERT expression, cellular immortalization and tumorigenesis in many types of cancer including glioma. The work proposed in Project 3 will lay the groundwork for the development of mutant TERT promoter-based therapeutics by assessing the uniformity of TERT promoter mutations in human glioma samples, by directly defining the importance of GABP in TERT activation, and by devising ways to increase cell death following TERT silencing. Project 4 is a new project based on the observation that inhibition of the downstream mTOR target 4EBP is critical for effective growth suppression of PI3K-driven glioblastoma, and that clinical failure of PI3K pathway-targeted therapeutics in glioblastoma is the result insufficient sustained 4EBP suppression. Accordingly Project 4 investigators synthesized an entirely new class of molecules that provide sustained 4EBP suppression and growth inhibition in vivo, and in this project will define the optimal glioma target population for the drug, will optimize the efficacy of the lead agent, and propose the first clinical trial of this new class of agents in glioma patients. This SPORE proposal also requests continued support for the extremely important Career Enhancement and Developmental Research Programs, and for three Cores (Administrative, Biospecimen/Pathology, and Biostatistics and Clinical) that will support the efforts of the four projects. By addressing the overall specific objectives described, the research proposed in this Brain Tumor SPORE application has a high likelihood of changing the way we detect, diagnose, and treat brain cancer.