The Immortality and Evolution of Adult Brain Tumors

项目摘要 Costello实验室研究了脑肿瘤中的细胞永生和进化，目标是将其转化为 将我们的发现转化为新疗法我在我们的研究中发挥着重要作用，以了解和克服 基因组和表观基因组肿瘤内异质性，由肿瘤演变驱动，是治疗的基础 失败一个翻译目标是鉴定产生免疫原性新抗原的突变， 目前在整个肿瘤，开发个性化的免疫疗法与博士合作。 冈田与一个跨学科的临床团队合作，我们开发了一种独特的三维整体肿瘤 采样方法，在该方法中，我们获得10个空间映射样本，每个肿瘤由 神经外科医生最大限度地代表整个肿瘤。我们已经开始应用基因组， 转录组和T细胞受体（TCR）测序数据I从这些空间映射的样品产生 以鉴定存在于整个肿瘤中的免疫原性新抗原及其同源TCR。我也是一个 肿瘤永生研究的重要贡献者为了无限增殖，肿瘤细胞必须克服 正常的寿命限制在很大程度上是由端粒缩短决定的，端粒缩短是细胞分裂的结果， 缺乏端粒酶活性。80%的胶质母细胞瘤和许多其他癌症可以克服这一点 通过在端粒酶启动子中获得突变来实现细胞永生的寿命屏障 逆转录酶（TERT）。我们发现，TERT启动子突变激活了正常的 通过选择性募集转录因子GABP沉默TERT基因和端粒酶活性 它通常不调节TERT。使用GABP的实验靶向，我们表明， 在具有TERT启动子突变的细胞中选择性地降低表达，并且当与 化疗后，它显著降低了体内GBM的生长。目前，我正在研究一种新发现的 GABP亚基表达稳态控制及其与TERT调控的关系翻译这些 Costello博士与人共同创立了一家生物技术初创公司， 具有药物样性质的小分子，以突变依赖性方式减少TERT。除了 为实现这些转化目标，我的职责包括：（1） 管理和监督实验室的基础设施和肿瘤样本收集;（2）技术和 （3）确保所有的实验室研究都是安全进行的， （4）培训新的实验室成员和个人， 脑肿瘤中心。此R50应用程序要求为这些正在进行的活动提供工资支持，以推进 以下国家癌症研究所资助项目的科学目标：3-D空间方法发现基因组效应子 恶性转化过程中的免疫抑制（R 01 CA 244838）;脑肿瘤孢子P1 - A TERT启动子突变型胶质瘤的新治疗靶点（2 P50 CA 097257）。

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).