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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（由申请人提供）：胶质瘤是儿童期最常见的实体瘤，儿童胶质瘤是最常见的肿瘤之一。在儿科低级别胶质瘤（PLGG）中，丝裂原蛋白激酶（MAPK）和磷脂酰肌醇-3 '激酶（PI 3 K）信号传导的激活表明靶向这些级联反应的药物可能有效。该提案评估了对用于PLGG临床治疗的有希望的靶向药物的反应的分子基础，并结合了新型和可转化的组合疗法的临床前测试，以（1）确定PLGG中鉴定的每种分子畸变的最佳疗法，包括BRAF改变和最近描述的非BRAF融合基因，（2）克服先天性，对MAPK/ERK和PI 3 K/mTOR抑制剂的内在抗性和（3）解决PLGG环境中的获得性抗性。我们将利用依维莫司治疗复发性PLGG的多机构2期临床试验，将允许我们检验PI 3 K/mTOR激活将预测对mTOR抑制的响应的假设。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。我们假设PLGG的每种分子亚型都需要不同的靶向方法来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生成临床前和临床数据，为治疗PLGG的个性化组合方法奠定基础，这些数据将确定每种分子亚型的最佳药物组合，并使下一代临床试验成为可能，其中合理的药物组合在假设驱动的研究中给予适当的患者。