SPORE in Brain Cancer

摘要：总体 这种脑癌孢子更新应用的首要目标是改善臭名昭著的糟糕结果 胶质母细胞瘤(GBM)患者。这一目标将通过发展多学科来实现 和高度翻译性的研究计划，寻求发现并快速机械地翻译新奇 多样化的治疗战略，包括生物、免疫和靶向战略，并通过发展 预后和预测性生物标志物，为个体化的GBM治疗提供信息，同时还 通过基于遗传的流行病学研究探索少数民族人群的发病机制和风险。通过 为贯彻本研究计划的战略，当前资助期(2013-18年)的所有项目都有 成功地从试验台过渡到临床试验，包括测试一种新的溶瘤病毒Delta-24- RGD，在多个临床试验中；完成一种PI3K靶向制剂的生物终点第二阶段临床试验， BKM-120；满足IND要求，进行一种新的免疫调节p-STAT-3抑制剂的首次人体试验， WP1066；以及在临床试验数据集中验证预后生物标记物，同时也测试分子预测因子 对辐射的敏感性。在这份续订申请中，我们提出了三个翻译研究项目， 从我们目前孢子的成功有机进化而来，并得到四个关键任务的支持 核心(行政、病理学/生物库、生物统计学/生物信息学、动物学)。我们的发展 研究计划(DRP)和职业提升计划(CEP)继续作为新项目和 新调查员的入口。我们项目的目标是： 项目1：通过完成临床试验，开发Delta-24-RGD激活抗胶质瘤免疫的能力 将Delta-24-RGD与pembrolizumab结合，并通过测试新一代Delta-24-RGD病毒 配备免疫刺激分子：OX40L，GITRL和4-1BBL，同时分析抗Ad5抗体 对治疗有反应的生物标记物。 项目2：通过开发和临床测试一种新的GEM来攻击GBM的代谢脆弱性 氧化磷酸化抑制物(OxPhos)，IacS-010759，可有效杀死含有基因或 损害糖酵解的表观遗传突变(例如，ENO1缺失)，并通过评估新的低氧反应 PET探针，18F-FAZA，作为IACS-010759的OxPhos抑制和靶向结合的读数。 项目3：破译黑人和西班牙裔少数族裔胶质瘤的种系和体细胞基因组图谱 其预后和存活率与欧洲白人血统的GBM患者不同的人群。生殖系SNP 数据将与病例匹配肿瘤的广泛分子图谱相结合。详细的分析将是 以确定祖先的构成及其如何影响脑胶质瘤的风险和临床结果 少数族裔。

SUMMARY: OVERALL The overarching goal of this Brain Cancer SPORE renewal application is to improve the notoriously poor outcome of patients with glioblastoma (GBM). This goal will be achieved through the development of a multidisciplinary and highly translational research program that seeks to discover and rapidly translate novel and mechanistically diverse treatment strategies, including biological, immunological and targeted strategies, and by developing prognostic and predictive biomarkers that inform individualized approaches to GBM treatment, while also exploring pathogenesis and risk through genetic-based epidemiological studies in minority populations. By pursuing the strategies of this research program, all projects in the current funding period (2013-18) have successfully transitioned from the bench to clinical trials, including testing of a novel oncolytic virus, Delta-24- RGD, in multiple clinical trials; completing a biological-endpoint Phase II clinical trial of a PI3K-targeted agent, BKM-120; meeting IND requirements for a first-in-human trial of a new immune-modulatory p-STAT-3 inhibitor, WP1066; and validating prognostic biomarkers in clinical trial datasets, while also testing a molecular predictor of radiation sensitivity. In this renewal application we propose three translational research projects that organically evolved from the successes of our current SPORE, and which are supported by four mission-critical Cores (Administrative, Pathology/Biorepository, Biostatistics/ Bioinformatics, Animal). Our Developmental Research Program (DRP) and Career Enhancement Program (CEP) continue as incubators of new projects and portals for new investigators. The aims of our projects are: Project 1: Exploit the capacity of Delta-24-RGD to activate anti-glioma immunity by completing a clinical trial combining Delta-24-RGD with Pembrolizumab, and by testing next-generation Delta-24-RGD viruses that are armed with immune stimulatory molecules: OX40L, GITRL, and 4-1BBL, while analyzing anti-Ad5 antibodies as a biomarker in response to therapy. Project 2: Attack metabolic vulnerabilities of GBMs through the development and clinical testing of a novel inhibitor of oxidative phosphorylation (OxPhos), IACS-010759, that efficiently kills GBMs harboring genetic or epigenetic mutations that impair glycolysis (e.g. ENO1 deletions), and by evaluating a new hypoxia-responsive PET probe, 18F-FAZA, as a readout of OxPhos inhibition and target engagement of IACS-010759. Project 3: Decipher germline and somatic genomic landscape of gliomas in Black and Hispanic minority populations, whose prognosis and survival differ than GBM patients of White European descent. Germline SNP data will be combined with extensive molecular profiling in case-matched tumors. A detailed analysis will be performed to determine ancestry composition and how it influences risk for gliomas and clinical outcome in minorities.