SPORE: Targeted Therapies for Glioma

SPORE：神经胶质瘤的靶向治疗

• 批准号: 10696098
• 负责人: Tracy T Batchelor
• 金额: $ 220.79万
• 依托单位: BRIGHAM AND WOMEN'S 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10696098
• 关键词: 3-Dimensional; Address; Adjuvant; Adult; Adult Glioblastoma; Adult Glioma; Age; Agreement; Astrocytoma; Award; BRAF gene; Basic Science; Biology; Biometry; Boston; Brain; Brain-Derived Neurotrophic Factor; CDK4 gene; Cancer Center; Cancer Etiology; Cell Cycle Arrest; Cell Cycle Progression; Cells; Cessation of life; Child; Child Care; Childhood; Childhood Brain Neoplasm; Childhood Glioma; Clinical; Clinical Trials; Collaborations; Complement; Computational Biology; Cyclin D1; Dana-Farber Cancer Institute; Daphne plant; Development; Diagnosis; Doctor of Medicine; Doctor of Philosophy; Enzymes; Excision; Fostering; Funding; General Hospitals; Genetic; Genetically Engineered Mouse; Glioblastoma; Glioma; Growth; Hospitals; Human; Image; Immune checkpoint inhibitor; Immunotherapeutic agent; Immunotherapy; Independent Living; International; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Massachusetts; Metabolic; Methods; Modality; Molecular; Mutation; Nature; Neurons; Neurosurgeon; Oncologist; Operative Surgical Procedures; Pathology; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Persons; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Primary Brain Neoplasms; Protein Isoforms; Protein Kinase; Protein-Serine-Threonine Kinases; Quality of life; Recurrence; Reproducibility; Research Personnel; Research Project Grants; Resected; Science; Scientist; Signal Transduction; Structural Biologist; Survivors; Talents; Teaching Hospitals; Testing; Therapeutic; Time; Tumor Immunity; Tumor Tissue; Universities; Variant; Woman; Work; alpha ketoglutarate; antagonist; brain tissue; career; cell type; childhood cancer mortality; clinical imaging; efficacy study; flexibility; humanized mouse; imaging study; improved; in vivo; inhibitor; innovation; leukemia; medical schools; melanoma; mouse model; mutant; neuro-oncology; neuroligin 3; novel; novel strategies; novel therapeutics; professor; programmed cell death protein 1; programs; response; single cell sequencing; skills; small molecule; standard of care; targeted treatment; tool; translational scientist; tumor; tumor growth; tumor microenvironment; young adult

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.

这是丹纳法伯/哈佛大学癌症中心针对神经胶质瘤的 SPORE 计划的竞争性更新。 目标是通过以下方式提高患有这些肿瘤的儿童、年轻人和成人的护理标准 为此，哈佛医学院和博德研究所的基础科学家们使用了靶向疗法。 研究所与波士顿儿童医院、布莱根妇女医院的临床/转化研究人员合作 医院、达纳法伯癌症研究所和麻省总医院有四个项目： 项目一针对儿童低级别星形细胞瘤 (PLGA)，近 75% 的 PLGA 是由儿童低级别星形细胞瘤 (PLGA) 驱动的。 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 医学博士与结构生物学家 Michael Eck 医学博士、哲学博士将共同开发和测试大脑渗透剂。 BRAF 突变 PLGA 的靶向治疗项目二针对 IDH 突变神经胶质瘤。 IDH 突变神经胶质瘤通常会产生极高水平的“致癌代谢物”R-2-。 然而，利用正常人之间的 2-HG 含量差异进行治疗。 神经外科医生丹尼尔·卡希尔（Daniel Cahill）医学博士、博士和癌症尚未认识到恶性脑组织。 生物学家 William Kaelin 医学博士将解决这一治疗缺陷，项目三针对成人神经胶质瘤。 基础科学家 Jean Zhao 博士最近的研究表明，除了抑制细胞周期进程之外， CDK4/6拮抗剂促进抗肿瘤免疫并协同增强对检查点的反应 展望未来，赵博士将与神经肿瘤学家 Patrick Wen 医学博士一起检验这一假设。 脑渗透性 CDK4/6 抑制剂可以增强 GBM 的免疫治疗方法 项目四。 针对成人和儿童神经胶质瘤的神经元微环境。 神经生物学家 Michelle Monje 博士表明，神经元通过活动促进神经胶质瘤生长 调节 Neuroligin-3 (NLGN3) 分泌到肿瘤微环境中，基础科学家 Mario Suva， 医学博士、博士拥有多种细胞类型的单细胞测序的改进方法 Monje 和 Suva 将共同定义新切除的人类神经胶质瘤的微环境。 微环境NLGN3调节神经胶质瘤形成和进展的分子机制 并探索嵌入 NLGN3 要求的新治疗机会。 病理学核心将促进四个项目中工作的严谨性和可重复性 生物统计学和计算生物学的管理核心将启用和管理。 哈佛医学院、四所大学之间达成多项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影像研究。 该计划内通过向年轻研究人员颁发的年度职业提升奖来维持和更新 以及年度发展项目奖。