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：
8865159
负责人：
DAPHNE A. HAAS-KOGAN
金额：
$ 55.13万
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/8865159
关键词：
1-Phosphatidylinositol 3-Kinase Address Affect Automobile Driving BRAF gene Biological Biological Markers 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 Fibroblast Growth Factor Receptors Frequencies Generations Genetic Genomics Genotype Glioma Goals Growth In Vitro Individual MAP Kinase Gene MEKs Malignant - descriptor Malignant Neoplasms Mitogen-Activated Protein Kinase Inhibitor Mitogens Modeling Molecular 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 RAF1 gene Radiation Recurrence Resistance Risk SDZ RAD Signal Transduction Staging Subgroup Testing Time Tissues base chemotherapy clinical efficacy combinatorial follow-up fusion gene human FRAP1 protein in vivo Model inhibitor/antagonist insight mTOR Inhibitor mTOR inhibition melanoma mortality next generation novel pediatric patients pre-clinical precision medicine preclinical study public health relevance receptor response success targeted treatment therapeutic target 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（由申请人提供）：神经胶质瘤是儿童期最常见的实体瘤，其中儿童神经胶质瘤是最顽固的儿童低级别神经胶质瘤中丝裂原蛋白激酶（MAPK）和磷脂酰肌醇-3'激酶（PI3K）信号的激活。（PLGG）表明针对这些级联反应的药物可能有效，该提案评估了有希望的临床治疗靶向药物的分子基础。 PLGG 的研究，并结合了新型和可转化的联合疗法的临床前测试，以 (1) 为 PLGG 中发现的每种分子畸变确定最佳疗法，包括 BRAF 改变和最近描述的非 BRAF 融合基因，(2) 克服先天性、内在的耐药性MAPK/ERK 和 PI3K/mTOR 抑制剂以及 (3) 解决 PLGG 环境中的获得性耐药问题，我们将利用快速增长的多机构 2 期临床。依维莫司治疗复发性 PLGG 的试验，其中从所有儿童采集组织将使我们能够测试 PI3K/mTOR 激活将预测对 mTOR 抑制的反应的假设，我们将进一步利用我们最近在克隆迄今为止表征的所有 PLGG BRAF 融合基因以及最近描述的非 BRAF 融合基因方面的成功。 PLGG 的每种分子亚型都需要独特且单独的靶向方法，以最大限度地提高疗效并克服耐药性，我们的总体目标是通过产生 PLGG 的个性化组合方法来治疗。临床前和临床数据将确定每种分子亚型的最佳药物组合，并支持下一代临床试验，在假设驱动的研究中向适当的患者施用合理的药物组合。