Precision Medicine For Pediatric Low-Grade Gliomas

 描述(申请人提供)：胶质瘤是最常见的儿童实体瘤，儿童胶质瘤是最顽固的。在儿童低级别胶质瘤(PLGG)中，丝裂原蛋白激酶(MAPK)和磷脂酰肌醇-3‘激酶(PI3K)信号均被激活，这表明针对这些级联反应的药物可能有效。这项建议评估了对有望用于临床治疗PLGGS的靶向药物的反应的分子基础，并纳入了新型和可转化联合疗法的临床前测试，以(1)确定针对PLGG中发现的每一种分子异常的最佳治疗方法，包括BRAF改变和最近描述的非BRAF融合基因，(2)克服对MAPK/ERK和PI3K/mTOR抑制剂的先天和内在耐药性，以及(3)解决PLGG环境中的获得性耐药性。我们将利用一项快速积累的多机构埃博利莫斯治疗复发性PLGG的2期临床试验，在该试验中，从所有儿童身上获取组织 将使我们能够检验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所有迄今具有特征的PLGG BRAF融合以及最近描述的非BRAF融合基因方面的成功。我们假设，PLGG的每个分子亚型都需要一种不同的、单独的靶向方法，以最大限度地提高疗效和克服耐药性。我们的总体目标是通过生成临床前和临床数据为治疗PLGGs奠定基础，这些数据将确定每个分子亚型的最佳药物组合，并使下一代临床试验能够在假设驱动的研究中将合理的药物组合应用于适当的患者。

 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.