The Immortality and Evolution of Adult Brain Tumors

成人脑肿瘤的永生和进化

• 批准号: 10517210
• 负责人: Chibo Hong
• 金额: $ 17.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517210
• 关键词: 3-Dimensional; Address; Adult; Biotechnology; Brain Neoplasms; Cell division; Cells; Clinical; Collaborations; Data; Ensure; Evolution; Failure; Funding; Genes; Genomics; Glioblastoma; Glioma; Goals; Growth; Human; Immune response; Immunogenomics; Immunosuppression; Individual; Infrastructure; Laboratory Research; Longevity; Malignant - descriptor; Malignant Neoplasms; Maps; Mutation; Neurosurgeon; Patients; Pharmaceutical Preparations; Play; Proliferating; Property; RNA-Directed DNA Polymerase; Regulation; Request for Applications; Research; Research Project Grants; Role; Sampling; Scientific Advances and Accomplishments; T cell receptor repertoire sequencing; T-Cell Receptor; Telomerase; Telomere Shortening; Therapeutic; Training; Translating; Tumor Volume; Wages; chemotherapy; epigenomics; immunogenic; in vivo; member; method development; mutant; neoantigens; neoplastic cell; new therapeutic target; novel therapeutics; personalized immunotherapy; promoter; recruit; sample collection; small molecule; targeted treatment; technology development; transcription factor; transcriptomics; translational goal; tumor; tumor heterogeneity

PROJECT ABSTRACT The Costello lab investigates cellular immortality and evolution in brain tumors with the goal of translating our discoveries into new therapies. I play an essential role in our studies to understand and overcome the genomic and epigenomic intra-tumor heterogeneity, driven by tumor evolution, that underlies therapeutic failures. One translational goal is to identify mutations that produce immunogenic neoantigens that are present throughout the whole tumor, to develop personalized immunotherapies in collaboration with Dr. Okada. Working with an interdisciplinary clinical team, we developed a unique, 3-dimensional whole tumor sampling approach in which we obtain 10 spatially mapped samples per tumor selected by the neurosurgeon to maximally represent the whole tumor. We have begun applying the genomic, transcriptomic and T cell receptor (TCR) sequencing data I produced from these spatially mapped samples to identify immunogenic neoantigens and their cognate TCR present throughout the tumor. I am also a significant contributor to our tumor immortality studies. To proliferate indefinitely, tumor cells must overcome the normal limits on lifespan dictated in large part by telomere shortening, a consequence of cell divisions in the absence of telomerase activity. Eighty percent of glioblastoma and many other cancers overcome this lifespan barrier to achieve cellular immortality by acquiring a mutation in the promoter of Telomerase Reverse Transcriptase (TERT). We discovered that the TERT promoter mutation activates the normally silent TERT gene and telomerase activity through selective recruitment of GABP, a transcription factor which does not normally regulate TERT. Using experimental targeting of GABP, we showed that TERT expression is reduced selectively in cells with the TERT promoter mutation, and when combined with chemotherapy, it dramatically reduces GBM growth in vivo. Currently, I am studying a newly discovered homeostatic control on GABP subunit expression and its relationship to TERT regulation. To translate these mechanistic studies into a new therapy, Dr. Costello co-founded a biotech startup which has discovered small molecules with drug-like properties that reduce TERT in a mutation dependent manner. In addition to performing bench research to address these translational goals, my responsibilities include: (1) management and oversight of the lab’s infrastructure and tumor sample collection; (2) technology and methods development for the group; (3) ensuring that all laboratory research is conducted safely in accordance with regulatory requirements; and (4) training new lab members and individuals throughout the Brain Tumor Center. This R50 application requests salary support for these ongoing activities to advance the scientific goals of the following NCI-funded projects: 3-D spatial approach to discover genomic effectors of immunosuppression during malignant transformation (R01 CA244838); The Brain Tumor SPORE P1 – A New Therapeutic Target for TERT Promoter Mutant Glioma (2P50CA097257).

项目摘要 Costello Lab研究了脑肿瘤中的细胞永生和进化，目的是翻译 我们发现了新疗法。我在我们的研究中扮演着重要的角色，以理解和克服 肿瘤进化驱动的基因组和表观基因组内异质性，这是治疗基础的 失败。一个翻译目标是识别产生免疫原性新抗原的突变 在整个肿瘤中存在，以与博士合作开发个性化的免疫疗法。 冈田。与跨学科临床团队合作，我们开发了一个独特的三维整体肿瘤 采样方法，我们每次选择10个空间映射样品。 神经外科医生至最大代表整个肿瘤。我们已经开始应用基因组， 我从这些空间映射的样品中得出的转录组和T细胞接收器（TCR）测序数据 在整个肿瘤中鉴定免疫原性的新抗原及其同源TCR。我也是一个 我们的肿瘤永生研究的重要贡献。要无限期增殖，必须克服肿瘤细胞 寿命的正常限制在很大程度上取决于端粒缩短，这是细胞分裂的结果 缺乏端粒酶活性。 80％的胶质母细胞瘤和许多其他癌症克服了这一点 通过在端粒酶启动子中获取突变来实现细胞永生的寿命屏障 逆转录酶（TERT）。我们发现TERT启动子突变正常激活 通过选择性募集GABP（转录因子）的无声TERT基因和端粒酶活性 通常不调节tert。使用GABP的实验靶向，我们证明了TERT 用TERT启动子突变选择性地降低表达，并与 化学疗法，它大大降低了体内GBM的生长。目前，我正在研究一个新发现的 对GABP亚基表达的稳态控制及其与TERT调节的关系。翻译这些 科斯特洛博士对新疗法的机械研究共同创立了一家生物技术初创公司，该初创公司发现了 具有类似药物特性的小分子以突变依赖性方式降低TERT。此外 进行基准研究以解决这些翻译目标，我的职责包括：（1） 对实验室的基础设施和肿瘤样本收集的管理和监督； （2）技术和 该小组的方法开发； （3）确保所有实验室研究都安全地进行 根据监管要求； （4）在整个过程中培训新的实验室成员和个人 脑肿瘤中心。此R50申请要求为这些正在进行的活动提供薪水支持 以下NCI资助的项目的科学目标：发现基因组效应的3-D空间方法 恶性转化期间的免疫抑制（R01 CA244838）；脑肿瘤孢子P1 - A TERT启动子突变胶质瘤的新治疗靶标（2P50CA097257）。