Brain Tumor SPORE Grant

项目摘要/摘要 这份孢子更新申请代表了跨学科调查团队的努力 来自加州大学旧金山分校海伦·迪勒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翻译研究。 这项孢子提案有三个总体具体目标：1)确定导致 脑癌存活的可能性；2)识别有助于预测的无创成像参数 胶质瘤患者的治疗反应；以及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翻译研究项目， 每个项目都由应用和基础研究人员团队推动，每个项目都打算创建新的工具和 在脑肿瘤的诊断和治疗中有用的治疗方式。项目1是一项新的研究 受之前孢子资助的分子特征鉴定成功的激励(TERT启动子 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，以及 与其他人的工作一起，导致了世卫组织胶质瘤分类标准的修改。项目1 研究人员现在假设，对各种循环中髓系细胞水平的分析，而不是 肿瘤分子特征，可能在鉴别IDH-野生型预后方面取得进展 胶质母细胞瘤后占一定的临床特征。他们将使用一种 他们首创的一种方法，定义和量化来自新鲜或 基于免疫细胞基因组DNA甲基化模式的冰冻外周血--一个新领域 这项研究被称为免疫甲基组学。项目2是一项新的研究，部分是由以前的孢子- 资助的研究使用核磁共振成像来非侵入性地确定代谢物稳态水平的变化 这与低级别胶质瘤的进展有关。在项目2中，调查人员假设使用 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无创性地区分正常和 人脑胶质母细胞瘤背景下的脑、肿瘤和胶质细胞增生症。项目3是一项新的研究，从 科斯特洛实验室的开创性工作将GABP确定为唯一的转录因子 结合突变的TERT启动子并驱动TERT的表达，细胞永生化和 肿瘤发生在许多类型的癌症中，包括胶质瘤。项目3中提出的工作将为 通过评估突变的TERT启动子为基础的治疗学的发展 人胶质瘤样本中TERT启动子突变的一致性，通过直接定义TERT启动子突变的重要性 GABP在TERT激活中的作用，以及通过设计方法增加TERT沉默后的细胞死亡。 项目4是一个新项目，基于对下游mTOR目标的抑制 4EBP对于有效抑制PI3K驱动的胶质母细胞瘤的生长至关重要，临床应用失败 PI3K通路靶向治疗胶质母细胞瘤是持续4EBP不足的结果 压制。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，在这个项目中将定义 最佳的胶质瘤靶向人群的药物，将优化先导剂的疗效，并建议 这类新药物在胶质瘤患者中的首次临床试验。这份孢子提案还要求 继续支持极其重要的职业提升和发展研究 计划，以及三个核心(行政、生物医学/病理学、生物统计和临床) 这将支持这四个项目的努力。通过解决所描述的总体具体目标， 在这项脑瘤孢子应用中提出的研究很有可能改变 我们发现、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.