Precision Medicine For Pediatric Low-Grade Gliomas

儿科低级别胶质瘤的精准医学

基本信息

批准号：
9334330
负责人：
DAPHNE A. HAAS-KOGAN
金额：
$ 52.02万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9334330
关键词：
1-Phosphatidylinositol 3-Kinase Address Affect Automobile Driving BRAF gene Biological Cells Central Nervous System Neoplasms Child Childhood Childhood Glioma Childhood Solid Neoplasm Clinical Data Clinical Research Clinical Treatment Clinical Trials Cloning Combined Modality Therapy Data Dependency Drug Combinations Enrollment Exhibits FRAP1 gene Fibroblast Growth Factor Receptors Frequencies Generations Genetic Genomics Genotype Glioma Goals Growth In Vitro Individual Malignant - descriptor Malignant Neoplasms Mitogens Modeling Molecular Molecular Abnormality Molecular Profiling Morbidity - disease rate Mutation Pathway interactions Patients Phase II Clinical Trials Phosphotransferases Pilocytic Positioning Attribute Pre-Clinical Model Preclinical Testing Predisposition Protein Kinase Protein Kinase Inhibitors RAF1 gene Radiation Recurrence Resistance Risk SDZ RAD Signal Transduction Subgroup Testing Time Tissues base chemotherapy clinical efficacy combinatorial follow-up fusion gene in vivo Model inhibitor/antagonist insight mTOR Inhibitor mTOR inhibition melanoma molecular subtypes mortality next generation novel pediatric patients personalized approach personalized strategies pre-clinical precision medicine preclinical study predicting response protein kinase inhibitor public health relevance receptor response response biomarker success targeted agent targeted treatment tool treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Gliomas are the most common solid tumors of childhood, with pediatric gliomas among the most recalcitrant. Activation of both mitogen protein kinase (MAPK) and phosphatidylinositol-3' kinase (PI3K) signaling in pediatric low-grade gliomas (PLGG) indicates possible efficacy for agents that target these cascades. This proposal assesses molecular underpinnings of response to promising targeted agents for clinical treatment of PLGGs, and incorporates preclinical testing of novel and translatable combination therapies to (1) define the best therapy for each molecular aberration identified in PLGGs, including BRAF alterations and recently described non-BRAF fusion genes, (2) overcome innate, intrinsic resistance to MAPK/ERK and PI3K/mTOR inhibitors and (3) address acquired resistance in the PLGG setting. We will capitalize on a rapidly accruing multi-institutional phase 2 clinical trial of everolimus for recurrent PLGGs in which acquisition of tissue from all children will allow us to test the hypothesis that PI3K/mTOR activation will predict response to mTOR inhibition. We will further capitalize on our recent success in cloning all PLGG BRAF-fusions characterized to date as well as recently described non-BRAF fusion genes. We hypothesize that each molecular subtype of PLGG will require a distinct and separate targeted approach to maximize efficacy and overcome resistance. Our overall goal is to set the stage for a personalized combinatorial approach for the treatment of PLGGs by generating pre-clinical and clinical data that will determine the best combination of agents for each molecular subtype and enable the next generation of clinical trials in which rational drug combinations are administered to appropriate patients in hypothesis-driven studies.

描述（由适用提供）：神经胶质瘤是最常见的童年实体瘤，在最顽固的小儿胶质瘤中是最常见的。在小儿低级神经胶质瘤（PLGG）中激活有丝分裂原蛋白激酶（MAPK）和磷脂酰肌醇3'激酶（PI3K）信号传导，这表明针对这些级联的药物可能效率。 This proposal assesses molecular underpinnings of response to promised targeted agents for clinical treatment of PLGGs, and incorporates preclinical testing of novel and translateable combination therapies to (1) define the best therapy for each molecular aberration identified in PLGGs, including BRAF alterations and recently described non-BRAF fusion genes, (2) overcome innate, intrinsic resistance to MAPK/ERK and PI3K/mTOR抑制剂和（3）地址在PLGG设置中获得的抗性。我们将利用快速累积的依维莫司的多机构2期临床试验，用于复发PLGG，其中所有儿童都从所有儿童中获取组织我们将允许我们检验以下假设：PI3K/MTOR激活将预测对MTOR抑制的反应。我们将进一步利用我们最近在克隆迄今为止的所有PLGG BRAF合并以及最近描述的非BRAF融合基因的成功。我们假设PLGG的每个分子亚型都需要采用独特而独立的靶向方法来最大化效率和克服电阻。我们的总体目标是通过生成临床前和临床数据来为一种个性化的组合方法奠定阶段，以确定每个分子亚型的剂的最佳组合，并使下一代临床试验能够在假设驱动的研究中对适当的患者施用合理的药物组合。