SPORE: Targeted Therapies for Glioma

我们在Dana-Farber/哈佛癌症中心提出了一项关于成人胶质母细胞瘤的孢子倡议。 我们的目标是通过对这类癌症使用有针对性的治疗来提高护理标准。为此，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综合医院的临床/翻译研究人员一起工作。这一倡议得到了病理学、生物统计学和行政管理中心的支持，并包括职业和发展计划。该研究计划使用临床材料并利用一些临床试验从四个不同的方面攻击胶质母细胞瘤： 项目一的目标是肿瘤血管系统。癌症生物学家Rakesh Jain博士和神经肿瘤学家Tracy Batchelor医学博士解决了目前血管为基础的胶质母细胞瘤治疗的僵局。为什么患者对贝伐单抗的反应通常是短暂的和边缘的？Jain和Batchelor将检验这样一个假设，即通过同时或顺序抑制血管生成素-2信号转导通路，可以增强对血管内皮生长因子途径抑制剂的反应。 项目二针对的是PI3K信号轴--一种在大约50%的胶质母细胞瘤中被激活的信号通路。生物化学家Tom Roberts博士(PI3K的共同发现者)和神经肿瘤学家Patrick wen医学博士致力于解决有关胶质母细胞瘤中PI3K信号的基本问题，这些问题一旦解决，将极大地优化使用小分子PI3K拮抗剂治疗这些肿瘤。 项目三以IDH途径为目标。恶性胶质瘤，包括胶质母细胞瘤，可能含有异柠檬酸脱氢酶1(IDH1)的功能获得突变，导致2-羟基戊二酸(2-HG)的积聚促进肿瘤的发生。分子生物学家威廉·凯林(医学博士)和神经外科医生丹尼尔·卡希尔(医学博士)将利用临床材料验证这样一种假设，即对2-HG水平的非侵入性测量可以作为IDH突变酶活性的替代指标，而以IDH突变和2-HG为靶点可以为恶性胶质瘤患者提供突破性治疗。 四号项目攻击的是寡核苷酸转录因子。分子生物学家查克·斯泰尔斯博士证明了胶质形成转录因子Orig2和P53之间的对立关系。在这些发现的基础上，斯泰尔斯和放射肿瘤学家、医学博士杰伊·勒弗勒将使用临床材料来验证这样一种假设，即抑制Opol2将提高大多数胶质母细胞瘤(~75%)的辐射敏感性，这些胶质母细胞瘤保留了结构完整的p53基因。

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.