SPORE: Targeted Therapies for Glioma

这是达纳-法伯/哈佛癌症中心关于胶质瘤的孢子倡议的竞争性更新。我们的 目标是通过以下途径提高儿童、年轻人和成人对这些肿瘤的护理标准 靶向治疗的使用。为此，来自哈佛医学院和博德大学的基础科学家 研究所与波士顿儿童医院、布里格姆和妇女医院的临床/翻译研究人员合作 医院、达纳-法伯癌症研究所和马萨诸塞州综合医院。共有四个项目： 项目一针对儿童低级别星形细胞瘤(PLGA)。近75%的PLGA是由 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Karen Wright，M.D.和结构生物学家Michael Eck，M.D.，Ph.D.将开发和测试脑渗透剂 针对BRAF突变的PLGA的靶向治疗。计划两个目标-IDH突变型胶质瘤 通常发生在年轻人身上。IDH突变的胶质瘤产生极高水平的“肿瘤代谢物”R-2- 羟基戊二酸(2-HG)。然而，治疗开发的差异2-HG含量之间的正常 而恶性脑组织还没有被认识到。神经外科医生丹尼尔·卡希尔，医学博士和癌症 生物学家威廉·凯林医学博士将解决这一治疗漏洞。三号项目针对的是成人胶质瘤。 基础科学家赵珍博士最近的研究表明，除了抑制细胞周期进程外， CDK4/6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。展望未来，赵博士和神经肿瘤学家帕特里克·温医学博士将检验这一假说 脑穿透性CDK4/6抑制剂可以加强对GBM的免疫治疗。项目四 针对成人和儿童神经胶质瘤的神经微环境。神经肿瘤学家与发育 神经生物学家Michelle Monje，M.D.，Ph.D.表明，神经元通过活动促进胶质瘤生长- 调节神经连接蛋白-3(NLGN3)向肿瘤微环境的分泌。基础科学家马里奥·苏瓦， M.D.，Ph.D.拥有完善的单细胞测序方法，用于在 新切除的人脑胶质瘤的微环境。Monje和Suva将共同努力，定义 微环境NLGN3调控胶质瘤形成和发展的分子机制 并探索嵌入NLGN3要求的新的治疗机会。 在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 以及生物统计学和计算生物学。管理核心将启用和管理 哈佛医学院、四所大学之间的多个联盟协议和合作互动 参与哈佛大学教学医院，并促进临床试验和成像研究。智力活力 在该计划内，通过向年轻调查人员颁发年度职业发展奖来维持和更新 和年度发展项目奖。

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.