SPORE: Targeted Therapies for Glioma

SPORE：神经胶质瘤的靶向治疗

• 批准号: 8918528
• 负责人: Tracy T Batchelor
• 金额: $ 216.7万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918528
• 关键词: Accounting; Address; Adult; Adult Glioblastoma; Age-Years; Angiopoietin-2; Animal Model; Area; Biomedical Engineering; Biometry; Blood; Blood Vessels; Brain; Brain Neoplasms; Cancer Center; Cancer Etiology; Cause of Death; Cell Line; Cell physiology; Cells; Cessation of life; Chromatin Structure; Clinical; Clinical Research; Clinical Trials; Communities; Comprehensive Cancer Center; Consent Forms; Core Facility; Dana-Farber Cancer Institute; Development; Dioxygenases; Disease; Doctor of Philosophy; Drug Targeting; Enrollment; Enzymes; Epigenetic Process; Funding; Gene Expression; General Hospitals; Genes; Genomics; Glioblastoma; Glioma; Hospitals; Human; Human Genome; Image; Imaging technology; Institutes; Institutional Review Boards; Isocitrate Dehydrogenase; Lipids; Magnetic Resonance Spectroscopy; Malignant Glioma; Malignant Neoplasms; Massachusetts; Measurement; Molecular; Mus; Mutation; Neurosurgeon; New Approaches to Brain Tumor Therapy Consortium; North American Brain Tumor Consortium; Oncologist; Other Genetics; Outcome; PTEN gene; Pathology; Pathway interactions; Patients; Penetrance; Phosphotransferases; Population; Production; Protein Isoforms; Proteins; Protocols documentation; Public Health Schools; Radiation Oncologist; Radiation Tolerance; Recurrence; Research; Research Personnel; Resistance; Resources; Scientist; Signal Pathway; Signal Transduction; Signal Transduction Pathway; TP53 gene; Teaching Hospitals; Testing; Therapeutic; Tissue Banking; Tissue Banks; United States National Institutes of Health; Vascular Endothelial Growth Factors; Vascular System; Visit; Woman; Work; Xenograft procedure; alpha ketoglutarate; angiogenesis; base; bevacizumab; cancer type; career; clinical material; enzyme activity; gain of function; gain of function mutation; improved; in vivo; inhibitor/antagonist; loss of function; medical schools; men; middle age; mutant; neuro-oncology; new technology; novel; programs; response; small molecule; standard of care; targeted treatment; temozolomide; therapeutic target; transcription factor; tumor; tumorigenesis

We propose a SPORE initiative on adult glioblastoma at the Dana-Farber/Harvard Cancer Center (DF/HCC). Our objective is to improve the standard of care through the use of targeted therapies for this type of cancer. Towards this end, basic scientists from Harvard Medical School have joined with clinical/translational investigators from Brigham and Women's Hospital, Dana-Farber Cancer Institute and Massachusetts General Hospital. This initiative is supported by central cores for Pathology, Biostatistics and Administration and includes career and developmental programs. The study plan uses clinical materials and exploits a number of clinical trials to attack glioblastoma on four distinct fronts: Project one targets the tumor vascular system. A cancer biologist, Rakesh Jain, PhD and a neurooncologist, Tracy Batchelor, MD address a current impasse in vascular-based therapies for glioblastoma. Why are patient responses to bevacizumab generally transient and marginal? Jain and Batchelor will test the hypothesis that responses to VEGF pathway inhibitors can be augmented by concurrent or sequential suppression of the angiopoietin-2 signal transduction pathway. Project two targets the PI3K signaling axis - a signaling pathway that is activated in ~50% of glioblastomas. Biochemist Tom Roberts, PhD (a co-discoverer of PI3K) and neuro-oncologist Patrick Wen, MD address fundamental issues regarding PI3K signaling in glioblastoma that - when resolved - will greatly optimize the treatment of these tumors with small molecule antagonists of PI3K. Project three targets the IDH pathway. Malignant gliomas, including glioblastomas, may harbor gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1) resulting in accumulation of 2-hydroxyglutarate (2- HG) promoting tumorigenesis. Molecular biologist William Kaelin, MD and neurosurgeon Daniel Cahill, MD, PhD will use clinical material to test the hypothesis that non-invasive measurement of 2-HG levels can serve as a surrogate for IDH mutant enzyme activity, and that targeting of IDH mutation and 2-HG can afford a breakthrough treatment for malignant glioma patients. Project four attacks the Olig2 transcription factor. Molecular biologist Chuck Stiles, PhD has demonstrated an oppositional relationship between the gliogenic transcription factor Olig2 and p53. Building upon these findings, Stiles and radiation oncologist Jay Loeffler, MD will use clinical materials to test the hypothesis that suppression of Olig2 will enhance radiation sensitivity of the major population of glioblastomas (~75%) that retain a structurally intact p53 gene.

我们提出了Dana-Farber/Harvard Cancer Center（DF/HCC）的成人胶质母细胞瘤的孢子倡议。 我们的目标是通过使用针对此类癌症的目标疗法来改善护理标准。为此，哈佛医学院的基础科学家与来自杨百翰和妇女医院，达纳 - 法伯癌症研究所和马萨诸塞州综合医院的临床/转化调查员一起。该倡议得到了病理，生物统计学和行政管理中央核心的支持，并包括职业和发展计划。该研究计划使用临床材料并利用许多临床试验来攻击四个不同方面的胶质母细胞瘤： 项目一个针对肿瘤血管系统。医学博士Tracy Batchelor的一名癌症生物学家Rakesh Jain，博士和神经科学家，针对胶质母细胞瘤的基于血管的疗法介绍了当前的僵局。为什么患者对贝伐单抗的反应通常是短暂和边缘的？ Jain和Batchelor将检验以下假设：对VEGF途径抑制剂的反应可以通过同时或顺序抑制Angiopoietin-2信号转导途径来增强。 项目第二个目标是PI3K信号轴 - 在约50％的胶质母细胞瘤中激活的信号通路。生物化学家汤姆·罗伯茨（PI3K的共同发现者）和神经综合学家帕特里克·温（Patrick Wen），MD解决了有关胶质母细胞瘤中PI3K信号传导的基本问题 - 解决后，这些问题将极大地优化PI3K的小分子拮抗剂对这些肿瘤的处理。 项目三个目标是IDH途径。恶性神经胶质瘤，包括胶质母细胞瘤，可能在异位酸脱氢酶1（IDH1）中携带功能增益突变，从而导致2-羟基羟戊二酸酯（2-HG）促进肿瘤发生。分子生物学家William Kaelin，医学博士和神经外科医师Daniel Cahill，医学博士，博士将使用临床材料来检验以下假设：2-HG水平的非侵入性测量可以作为IDH突变酶活性的替代品，以及对IDH突变和2-HG的靶向靶向不良患者的靶向不良患者。 项目四攻击Olig2转录因子。分子生物学家Chuck Stiles博士表明神经胶质转录因子Olig2和p53之间存在对立关系。在这些发现的基础上，马里兰州的Stiles和辐射肿瘤学家Jay Loeffler将使用临床材料来测试抑制Olig2的假设，即OLIG2的抑制作用将增强胶质母细胞瘤（〜75％）的辐射敏感性，该群体保留了结构上完整的p53基因。