Targeted therapy in ex vivo medulloblastoma/PNET

描述（由申请人提供）：髓母细胞瘤和原始神经外胚层（PNET）脑肿瘤患儿被分为平均高危组和高危组，以便治疗强度可以量身定制。不幸的是，对患者进行分层的方法并不完善，因此，被归类为“平均风险”的儿童中有大约25%未能接受治疗并死于疾病。我们已经确定P27缺失是一种生物标志物，可以识别大多数这些儿童，并可用于适当地将他们置于高风险类别，在那里他们将接受强化治疗，增加生存机会。另一个临床问题是PNET患者在临床试验中与成神经管细胞瘤患者分组，治疗方法相同。我们最近了解到PNET肿瘤在分子上与成神经管细胞瘤不同，并且PNET患者对为成神经管细胞瘤患者量身定制的治疗反应不佳。针对该疾病定制sPNET治疗的关键障碍是缺乏相关的sPNET临床前模型。我们已经产生了患者来源的sPNET干细胞培养和原位小鼠模型，并使用这些来识别fda批准的药物，这些药物在临床前研究中比目前使用的药物更有效。在这项更新申请中，我们的具体目标是：1)确定髓母细胞瘤和sPNET患者治疗失败的预后指标。2)为未来的临床试验确定靶向治疗的优先顺序。预期结果是：1)我们将进一步完善适合患者分层的分子生物标志物，在一项对300名患者的前瞻性分析中；2)我们将建立与临床相关的sPNET和高风险髓母细胞瘤临床前模型。3)根据我们的记录，我们将基于超过目前临床前结果进入临床试验的所有标准的研究，促进人类sPNET和高风险髓母细胞瘤试验方案。这个

DESCRIPTION (provided by applicant): Children with medulloblastoma and primitive neuroectodermal (PNET) brain tumors are divided into average- and high-risk groups so that therapy intensity can be tailored. Unfortunately, the methods for stratifying patients are imperfect, so that > 25% of children categorized as "average risk" fail therapy and die of disease. We have identified P27 loss as a biomarker that identifies most of these children and could be used to appropriately place them in the high-risk category, where they would receive intensified therapy increasing survival chances. Another clinical problem is that PNET patients are grouped with medulloblastoma patients in clinical trials and treated identically. We have recently learned that PNET tumors are molecularly distinct from medulloblastomas and that PNET patients respond poorly to therapy that has been tailored for medulloblastoma patients. The critical barrier to tailoring sPNET therapy to the disease has been the lack of relevant sPNET pre-clinical models. We have generated patient-derived sPNET stem cell cultures and orthotopic mouse models and have used these to identify FDA-approved drugs that are more efficacious in pre-clinical studies than currently used drugs. In this renewal application, our Specific Aims are: 1) To identify prognostic indicators of therapy failure for medulloblastoma and sPNET patients. 2) To prioritize targeted therapies for future clinical trials. The expected outcomes are: 1) that we will further refine molecular biomarkers suitable for patient stratificatin in a prospective analysis of > 300 patients; 2) that we will generate clinically relevant sPNET and high risk medulloblastoma pre-clinical models and 3) consistent with our track record, we will promote a regimen for human sPNET and high risk medulloblastoma trials based on studies that exceed all current standards for advancement of pre-clinical results into clinical trials. The significance is that we will ultimately abandon an archaic patient stratification scheme in favor o a biologically-based strategy that appropriately directs patients into tailored therapy and that sPNET patients will be treated with therapeutic regimens that are based on relevant pre-clinical and clinical data. Ultimately both will yield higher cure rates and limit toxicity in pediatric bran tumor patients.