SPORE: Targeted Therapies for Glioma

这是达纳-法伯/哈佛癌症中心关于神经胶质瘤的SPORE倡议的竞争性更新。我们 目的是通过以下措施提高儿童、青年和成人肿瘤患者的护理标准： 使用靶向治疗。为此，来自哈佛医学院和布罗德学院的基础科学家们 研究所与来自波士顿儿童医院、布里格姆和妇女医院的临床/翻译研究人员合作 医院，丹娜-法伯癌症研究所和马萨诸塞州总医院。有四个项目： 项目一针对儿童低级别星形细胞瘤（PLGA）。近75%的PLGA由以下因素驱动： 激活BRAF蛋白激酶的突变。临床医生/科学家Daphne Haas-Kogan，医学博士和凯伦 Wright，医学博士与结构生物学家迈克尔·埃克博士一起，博士将开发并测试大脑渗透剂 BRAF突变型PLGA的靶向治疗剂。项目二针对IDH突变型胶质瘤， 特别是在年轻人中。IDH突变型胶质瘤产生非常高水平的“癌代谢物”R-2- 羟戊二酸（2-HG）。然而，利用正常人与正常人之间的2-HG含量差异进行治疗是不可行的。 和恶性脑组织的可能性还没有被发现。神经外科医生丹尼尔卡希尔，医学博士，博士和癌症 生物学家威廉·凯林医学博士将填补这一治疗空白项目三针对成人胶质瘤。 基础科学家Jean Zhao博士最近的研究显示除了抑制细胞周期进程， CDK 4/6拮抗剂促进抗肿瘤免疫并协同增强对检查点的应答 抑制剂的展望未来，赵博士与神经肿瘤学家帕特里克温博士一起，将检验这个假设 脑渗透性CDK 4/6抑制剂可以增强GBM的免疫途径。项目四 靶向成人和儿童胶质瘤的神经元微环境。神经肿瘤学家和发育 神经生物学家Michelle Monje医学博士博士已经证明神经元通过活动促进神经胶质瘤的生长- 调节神经连接素-3（NLGN 3）分泌到肿瘤微环境中。基础科学家马里奥苏瓦， 医学博士、哲学博士已经改进了用于多种细胞类型的单细胞测序的方法， 新鲜切除的人胶质瘤的微环境。Monje和苏瓦将共同努力， 微环境NLGN 3调节胶质瘤形成和进展的分子机制 并探索嵌入NLGN 3需求的新治疗机会。 四个项目中进行的工作的严谨性和可重复性将由病理学核心培养 生物统计学和计算生物学。一个行政核心将使能和管理 多个联盟协议和哈佛医学院之间的合作互动，四个 参与哈佛教学医院，并促进临床试验和成像研究。智力活力 在该计划中，每年向年轻调查人员颁发职业提升奖， 以及年度发展项目奖。

This is the competing renewal of a SPORE initiative on glioma at Dana-Farber/Harvard Cancer Center. Our objective is to improve the standard of care for children, young adults, and adults with these tumors through the use of targeted therapies. Towards this end, basic scientists from Harvard Medical School and the Broad Institute join with clinical/translational investigators from Boston Children’s Hospital, Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Massachusetts General Hospital. There are four projects: Project One targets pediatric low-grade astrocytomas (PLGAs). Nearly 75% of PLGAs are driven by activating mutations in the BRAF protein kinase. Clinician/scientists Daphne Haas-Kogan, M.D. and Karen Wright, M.D. together with structural biologist Michael Eck, M.D., Ph.D. will develop and test brain-penetrant targeted therapeutics for BRAF-mutant PLGAs. Project Two targets IDH-mutant gliomas which present typically in young adults. IDH-mutant gliomas produce extraordinarily high levels of the ‘oncometabolite’ R-2- hydroxyglutarate (2-HG). However, therapeutic exploitation of the differential 2-HG content between normal and malignant brain tissue has yet to be realized. Neurosurgeon Daniel Cahill, M.D., Ph.D. and cancer biologist William Kaelin, M.D. will address this therapeutic lacuna. Project Three targets adult gliomas. Recent studies by basic scientist Jean Zhao, Ph.D. show that in addition to suppressing cell cycle progression, CDK4/6 antagonists promote anti-tumor immunity and synergistically enhance the response to checkpoint inhibitors. Going forward, Dr. Zhao together with neuro-oncologist Patrick Wen, M.D. will test the hypothesis that brain penetrant CDK4/6 inhibitors can augment immunotherapeutic approaches to GBM. Project Four targets the neuronal microenvironment of adult and pediatric gliomas. Neuro-oncologist and developmental neurobiologist Michelle Monje, M.D., Ph.D. has shown that neurons promote glioma growth through activity- regulated secretion of neuroligin-3 (NLGN3) into the tumor microenvironment. Basic scientist Mario Suva, M.D, Ph.D. has refined methods for single cell sequencing of the multiple cell types within the microenvironment of freshly resected human gliomas. Working together, Monje and Suva will define the molecular mechanisms whereby microenvironmental NLGN3 modulates formation and progression of gliomas and explore a novel therapeutic opportunity embedded within the NLGN3 requirement. Rigor and reproducibility of work conducted in the four projects will be fostered by cores for Pathology and for Biostatistics and Computational Biology. An Administration core will enable and manage the multiple consortium agreements and collaborative interactions between Harvard Medical School, the four participating Harvard teaching hospitals and facilitate clinical trials and imaging studies. Intellectual vigor within the program is sustained and refreshed by annual Career Enhancement Awards to young investigators and by annual Developmental Project Awards.