SPORE in Brain Cancer

脑癌中的孢子

基本信息

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
项目类别：
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

项目摘要

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：总体脑癌 SPORE 更新应用程序的总体目标是改善众所周知的不良结果胶质母细胞瘤（GBM）患者。这一目标将通过多学科的发展来实现以及高度转化的研究计划，旨在发现并快速翻译新颖和机械的多样化的治疗策略，包括生物、免疫和靶向策略，并通过开发预后和预测生物标志物，为 GBM 治疗的个体化方法提供信息，同时也通过少数民族人群基于遗传的流行病学研究探索发病机制和风险。经过为贯彻本研究计划的战略，当前资助期间（2013-18）的所有项目均已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 PI3K 靶向药物的生物终点 II 期临床试验， BKM-120；满足新型免疫调节 p-STAT-3 抑制剂首次人体试验的 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因子辐射敏感性。在此更新申请中，我们提出了三个转化研究项目从我们当前 SPORE 的成功有机发展而来，并得到四个关键任务的支持核心（管理、病理学/生物样本库、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）继续作为新项目和新调查人员的门户。我们项目的目标是：项目1：通过完成临床试验，利用Delta-24-RGD激活抗神经胶质瘤免疫的能力将 Delta-24-RGD 与 Pembrolizumab 相结合，并通过测试下一代 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志物。项目 2：通过开发和临床测试一种新型药物来攻击 GBM 的代谢脆弱性氧化磷酸化 (OxPhos) 抑制剂，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 ENO1 缺失），并通过评估新的缺氧反应 PET 探针 18F-FAZA，作为 OxPhos 抑制和 IACS-010759 靶标参与的读数。项目 3：破译黑人和西班牙裔少数群体神经胶质瘤的种系和体细胞基因组图谱人群，其预后和生存率与欧洲白人血统的 GBM 患者不同。种系SNP 数据将与病例匹配肿瘤的广泛分子分析相结合。将会进行详细分析进行以确定祖先组成及其如何影响神经胶质瘤的风险和临床结果少数民族。