SPORE in Brain Cancer

摘要：总体 这个脑癌孢子更新应用程序的首要目标是改善臭名昭著的不良结果 胶质母细胞瘤（GBM）患者。这一目标将通过发展多学科的 和高度翻译的研究计划，旨在发现和快速翻译小说和机械 多样化的治疗策略，包括生物学、免疫学和靶向策略， 预后和预测生物标志物，为GBM治疗提供个性化方法，同时还 通过在少数群体中进行基于遗传学的流行病学研究，探索发病机制和风险。通过 为了实施这一研究计划的战略，目前资助期（2013-18年）的所有项目都 成功地从实验室过渡到临床试验，包括测试一种新型溶瘤病毒Delta-24- RGD，在多项临床试验中;完成PI 3 K靶向药物的生物学终点II期临床试验， BKM-120;符合IND对一种新型免疫调节性p-STAT-3抑制剂的首次人体试验的要求， WP1066;以及在临床试验数据集中验证预后生物标志物，同时还测试分子预测因子 辐射敏感性。在这次更新申请中，我们提出了三个转化研究项目， 从我们当前的SPORE的成功有机地演变而来，并得到四个关键任务的支持 核心（管理、病理学/生物储存库、生物统计学/生物信息学、动物）。我们的发展 研究计划（DRP）和职业提升计划（CEP）继续作为新项目的孵化器， 新调查员的门户网站我们项目的目标是： 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，并通过测试下一代Delta-24-RGD病毒， 配备免疫刺激分子：OX 40 L，GITRL和4-1BBL，同时分析抗Ad 5抗体作为 对治疗有反应的生物标志物。 项目2：通过开发和临床测试一种新的GBM， 氧化磷酸化抑制剂（OxPhos），IACS-010759，可有效杀死携带遗传或 损害糖酵解的表观遗传突变（例如，ENO 1缺失），并通过评估新的缺氧反应性 PET探针，18F-FAZA，作为OxPhos抑制和IACS-010759靶点结合的读数。 项目3：破译黑人和西班牙裔少数民族胶质瘤的种系和体细胞基因组景观 预后和存活率不同于白色欧洲血统的GBM患者。种系SNP 数据将与病例匹配肿瘤的广泛分子谱分析相结合。详细分析将在 进行，以确定祖先组成，以及它如何影响神经胶质瘤的风险和临床结果， 少数群体

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.