SPORE in Brain Cancer

脑癌中的孢子

• 批准号: 10005119
• 负责人: Juan Fueyo
• 金额: $ 209.48万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005119
• 关键词: Adult; Alleles; Animals; Antibodies; Area; Attention; Award; Back; Bioinformatics; Biological; Biological Markers; Biometry; Blood; Brain Neoplasms; Caring; Clinic; Clinical; Clinical Trials; Collaborations; Data; Data Set; Development; Disease; Environment; Epigenetic Process; European; Fostering; Funding; Genetic; Genomics; Glioblastoma; Glioma; Glycolysis; Goals; Grant; Hispanics; Home environment; Human; Hypoxia; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune response; Immunity; Immunotherapeutic agent; Immunotherapy; Impairment; Incidence; Incubators; K-Series Research Career Programs; Malignant neoplasm of brain; Malignant neoplasm of central nervous system; Mentors; Metabolic; Minority; Minority Groups; Mission; Molecular; Molecular Abnormality; Molecular Profiling; Mutation; Oncolytic viruses; Operative Surgical Procedures; Outcome; Oxidative Phosphorylation; Pathogenesis; Pathology; Patient-Focused Outcomes; Patients; Pattern; Phase I/II Clinical Trial; Phase II Clinical Trials; Phosphorylation Inhibition; Population; Population Study; Positron-Emission Tomography; Prognostic Marker; Radiation; Radiation Tolerance; Records; Research; Research Personnel; Research Project Grants; Resources; Risk; Safety; Sampling; Science; Single Nucleotide Polymorphism; Source; Stress; TNFSF4 gene; Testing; The Cancer Genome Atlas; Therapeutic; Time; Tissues; Translating; Translational Research; University of Texas M D Anderson Cancer Center; Virus; Work; base; bench to bedside; biobank; cancer diagnosis; career; chemotherapy; epidemiology study; first-in-human; flexibility; genome wide association study; improved; improved outcome; inhibitor/antagonist; innovation; meetings; multidisciplinary; next generation; novel; oncolysis; oncolytic adenovirus; outcome forecast; personalized approach; phase II trial; population based; predictive marker; programs; racial disparity; repository; research clinical testing; response; success; targeted agent; targeted treatment; translational research program; translational scientist; treatment strategy; tumor; underserved minority

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.

摘要：总体 这种脑癌孢子更新应用的总体目标是改善臭名昭著的效果不佳 胶质母细胞瘤（GBM）的患者。通过开发多学科，将实现此目标 以及高度转化的研究计划，旨在发现并迅速地翻译小说和机械 各种治疗策略，包括生物学，免疫学和靶向策略，并通过发展 预后和预测性的生物标志物为个性化的GBM治疗方法提供了信息，同时也 通过基于遗传的流行病学研究探索发病机理和风险。经过 追求该研究计划的策略，当前资助期（2013-18）的所有项目都已经 成功地从长凳过渡到临床试验，包括测试新型的溶瘤病毒，Delta-24-- RGD，在多个临床试验中；完成针对PI3K靶向药物的生物端II期临床试验， BKM-1220;满足新的免疫调节P-​​STAT-3抑制剂的首次人类试验的IND要求， WP1066;并验证临床试验数据集中的预后生物标志物，同时还测试分子预测指标 辐射灵敏度。在此续签应用中，我们提出了三个转化研究项目 从我们当前的孢子的成功中有机地演变出来，并由四个关键任务的支持 核心（行政，病理/生物术，生物统计学/生物信息学，动物）。我们的发展 研究计划（DRP）和职业增强计划（CEP）继续担任新项目的孵化器， 新调查员的门户。我们项目的目的是： 项目1：利用Delta-24-RGD的能力通过完成临床试验来激活抗脱脂瘤免疫力 将Delta-24-RGD与Pembrolizumab结合在一起，并通过测试下一代Delta-24-RGD病毒 用免疫刺激分子武装：OX40L，GITRL和4-1BBL，同时将抗AD5抗体分析为 响应治疗的生物标志物。 项目2：通过开发和临床测试，GBM的攻击代谢脆弱性 氧化磷酸化抑制剂（OXPHOS），IACS-010759，有效杀死具有遗传或 损害糖酵解的表观遗传突变（例如ENO1缺失），并通过评估新的缺氧反应性。 PET探测器，18F-FAZA，是IACS-010759的OXPHOS抑制和目标参与的读数。 项目3：黑色和西班牙裔少数族裔的胶质瘤的年系和躯体基因组景观 人群的预后和生存率与欧洲白人血统的GBM患者不同。种系SNP 在病例匹配的肿瘤中，数据将与广泛的分子分析相结合。详细的分析将是 执行以确定祖先组成及其如何影响神经胶质瘤和临床结果的风险 少数民族。