SPORE: Targeted Therapies for Glioma

我们建议在Dana-Farber/哈佛癌症中心（DF/HCC）对成人胶质母细胞瘤进行SPORE研究。 我们的目标是通过使用针对这种癌症的靶向治疗来提高护理标准。为此，来自哈佛医学院的基础科学家与来自布里格姆妇女医院、达纳-法伯癌症研究所和马萨诸塞州总医院的临床/翻译研究人员合作。该计划由病理学，生物统计学和管理中心核心支持，包括职业和发展计划。该研究计划使用临床材料，并利用一些临床试验在四个不同的方面攻击胶质母细胞瘤： 项目一针对肿瘤血管系统。癌症生物学家Rakesh Jain博士和神经肿瘤学家Tracy Batchelor博士解决了目前胶质母细胞瘤血管治疗的僵局。为什么患者对贝伐珠单抗的反应通常是短暂和轻微的？Jain和Batchelor将检验对VEGF通路抑制剂的反应可以通过同时或顺序抑制血管生成素-2信号转导通路来增强的假设。 项目二靶向PI 3 K信号轴-一种在约50%的胶质母细胞瘤中激活的信号通路。生物化学家Tom Roberts博士（PI 3 K的共同发现者）和神经肿瘤学家帕特里克温博士解决了胶质母细胞瘤中PI 3 K信号传导的基本问题，这些问题解决后将极大地优化这些肿瘤的小分子PI 3 K拮抗剂治疗。 项目三针对IDH途径。恶性胶质瘤，包括胶质母细胞瘤，可能在异柠檬酸脱氢酶1（IDH 1）中存在功能获得性突变，导致2-羟基戊二酸（2- HG）蓄积，促进肿瘤发生。分子生物学家William Kaelin，MD和神经外科医生丹尼尔卡希尔，MD，PhD将使用临床材料来测试以下假设：2-HG水平的非侵入性测量可以作为IDH突变酶活性的替代物，并且IDH突变和2-HG的靶向可以为恶性胶质瘤患者提供突破性治疗。 项目四攻击Olig 2转录因子。分子生物学家Chuck Stiles博士已经证明了胶质生成转录因子Olig 2和p53之间的对立关系。在这些发现的基础上，Stiles和放射肿瘤学家Jay Loeffler将使用临床材料来检验抑制Olig 2将增强保留结构完整的p53基因的胶质母细胞瘤（约75%）的主要群体的辐射敏感性的假设。

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.