Defining the role of BRAF in glioma initiation and maintenance

定义 BRAF 在神经胶质瘤发生和维持中的作用

基本信息

批准号：
8330403
负责人：
Sheri L Holmen
金额：
$ 39.7万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8330403
关键词：
7q34 Adult Adult Glioblastoma Adult Glioma Alleles Anaplastic astrocytoma BRAF gene Biological Biology Brain Neoplasms CDKN2A gene Cancer Etiology Cell Proliferation Cells Central Nervous System Neoplasms Cessation of life Child Childhood Childhood Astrocytic Tumor Childhood Glioma Classification Clinical Clinical Research Clinical Trials Coupled Cyclin-Dependent Kinase Inhibitor 2A DNA Data Development Disease Doxycycline Drug Delivery Systems Effectiveness Environment Gene Targeting Genes Genetic Suppression Genomic Instability Genomics Glioblastoma Glioma Gliomagenesis Human In Vitro Incidence Individual Investigation Knowledge Lead Lesion Link MEKs Maintenance Malignant - descriptor Malignant Glioma Malignant Neoplasms Mediator of activation protein Medicine Methods Mitogen-Activated Protein Kinases Modeling Molecular Molecular Profiling Morbidity - disease rate Mus Mutation Names Other Genetics Pathway interactions Patients Physiology Play Pre-Clinical Model Process Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt RNA Receptor Protein-Tyrosine Kinases Role Sampling Signal Pathway Signal Transduction Stimulus Stratification Survival Rate System Testing Tetracyclines The Cancer Genome Atlas Therapeutic Therapeutic Agents Therapeutic Intervention Validation World Health Organization base cancer care cell type drug development drug discovery fusion gene gene function glioma cell line improved in vivo in vivo Model inhibitor/antagonist mouse model mutant novel overexpression positional cloning research study response small molecule temozolomide treatment strategy tumor tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Gliomas are the most common primary central nervous system tumor, and the leading cause of cancer-related death in children, but the molecular mechanisms responsible for the development and progression of these tumors are far from being completely understood. The identification and validation of genes that cause disease is an essential first step in the drug discovery and development process. Activating mutations of BRAF have been identified in a significant number of human cancers and several recent studies have detected these lesions in both pediatric and adult gliomas of varying grades; however, the role of BRAF activation in glioma initiation, progression, and maintenance has not been validated. With the effective use of in vivo models, expensive drug-discovery experiments can be focused on the drug targets that are most likely to lead to effective therapeutics. Once a gene target or pathway is identified, the next step is to demonstrate that it plays a critical role in disease initiation, maintenance, or both. We performed a preliminary assessment of the role of activated BRAF in glioma development in vivo. We found that while BRAFV600E was not tumorigenic on its own, cooperation with cyclin-dependent kinase inhibitor 2a (Cdkn2a; Ink4a/Arf) loss or AKT activation leads to the formation of malignant gliomas that is context dependent. Based on these data, we hypothesize that BRAF or downstream signaling mediators may be relevant targets for therapy in both pediatric and adult gliomas with this alteration. Mouse reverse genetics has become a powerful approach for deciphering gene function and target validation in the natural environment of mammalian physiology and we will use this approach in combination with the tetracycline-regulated expression system to determine if BRAFV600E is required for the maintenance of gliomas in vivo in the context of Ink4a/Arf-deficiency. We will also perform mechanistic studies to determine if BRAF activation cooperates with other genetic alterations to promote gliomagenesis. Using expression profiling, a molecular signature will be generated to further define whether mutant BRAF defines a novel molecular subtype of GBM or clusters with a known glioma subtype. GBM subtypes based on differential activation of signaling pathways may not only assist with predicting response to therapy but may also allow for rational stratification of patients in clinical trials of targeted agents. Whether BRAF or relevant downstream signaling mediators can be productively targeted for therapeutic intervention in this disease has yet to be determined. Since this model can also be used to test therapeutic agents, we will evaluate the effectiveness of pharmacological inhibition of BRAFV600E in gliomas both in vitro and in vivo using pharmacological inhibitors of clinical importance. A better understanding of the biology of these gliomas will guide the development of new therapies to improve survival and reduce morbidity in these patients.

描述（申请人提供）：神经胶质瘤是最常见的原发性中枢神经系统肿瘤，也是儿童癌症相关死亡的主要原因，但导致这些肿瘤发生和进展的分子机制还远未完全了解。识别和验证导致疾病的基因是药物发现和开发过程中至关重要的第一步。 BRAF 的激活突变已在大量人类癌症中被发现，最近的几项研究也在不同级别的儿童和成人神经胶质瘤中检测到了这些病变；然而，BRAF 激活在神经胶质瘤发生、进展和维持中的作用尚未得到验证。通过有效利用体内模型，昂贵的药物发现实验可以集中在最有可能产生有效治疗的药物靶标上。一旦确定了基因靶点或途径，下一步就是证明它在疾病的发生、维持或两者中发挥着关键作用。我们对激活的 BRAF 在体内神经胶质瘤发育中的作用进行了初步评估。我们发现，虽然 BRAFV600E 本身不具有致瘤性，但与细胞周期蛋白依赖性激酶抑制剂 2a（Cdkn2a；Ink4a/Arf）缺失或 AKT 激活协同作用，会导致环境依赖性恶性神经胶质瘤的形成。基于这些数据，我们假设 BRAF 或下游信号传导介质可能是具有这种改变的儿童和成人神经胶质瘤治疗的相关靶点。小鼠反向遗传学已成为在哺乳动物生理学自然环境中破译基因功能和靶点验证的强大方法，我们将使用这种方法与四环素调节的表达系统相结合，以确定体内胶质瘤的维持是否需要 BRAFV600E在 Ink4a/Arf 缺乏的情况下。我们还将进行机制研究，以确定 BRAF 激活是否与其他基因改变共同促进神经胶质瘤发生。使用表达谱，将生成分子特征，以进一步确定突变体 BRAF 是否定义了 GBM 的新分子亚型或具有已知神经胶质瘤亚型的簇。基于信号通路差异激活的 GBM 亚型不仅可以帮助预测治疗反应，还可以在靶向药物的临床试验中对患者进行合理分层。 BRAF 或相关下游信号传导介质是否可以有效地针对这种疾病进行治疗干预尚未确定。由于该模型也可用于测试治疗药物，因此我们将使用具有临床意义的药理学抑制剂在体外和体内评估 BRAFV600E 在神经胶质瘤中药理学抑制的有效性。更好地了解这些神经胶质瘤的生物学将指导新疗法的开发，以提高这些患者的生存率并降低发病率。