Targeted therapy in ex vivo medulloblastoma/PNET

描述（由申请人提供）：髓母细胞瘤/PNET患儿目前接受手术、放疗和化疗治疗。这些治疗的幸存者经常遭受严重的长期毒性。我们的实验室已经在人类成神经管细胞瘤和小鼠成神经管细胞瘤模型的离体标本中显示，包括13-顺式维甲酸（RA）、环巴胺、notch通路抑制剂、组蛋白去乙酰化酶抑制剂和这些药物的组合在内的靶向治疗可诱导成神经管细胞瘤细胞死亡，以及目前用于这些患者的毒性更大的化疗药物。基于我们与13-cis类风湿性关节炎相关的研究结果，儿童肿瘤小组已经开展了一项全国性的III期临床试验来评估该药物的疗效。与该临床试验相关的生物学研究的广泛长期目标是：1)确定具有预后和预测价值的生物标志物，用于未来的临床试验；2)优先考虑未来临床试验的候选靶向疗法。本提案的具体目的是利用离体手术标本，1)确定预测高风险髓母细胞瘤/SPNETs治疗失败的生物标志物，2)为未来的临床试验确定靶向治疗的优先级。这项工作的意义在于，它是用更有效、毒性更低的替代方案取代目前儿科脑肿瘤治疗方式的直接手段。

DESCRIPTION (provided by applicant): Children with medulloblastoma/PNET are currently treated with surgery, radiation, and chemotherapy. Survivors often suffer severe long-term toxicity from these treatments. Our laboratory has shown in ex vivo specimens from human medulloblastoma and mouse medulloblastoma models that targeted therapies including 13-cis retinoic acid (RA), cyclopamine, notch pathway inhibitors, histone deacetylase inhibitors and combinations of these agents induce medulloblastoma cell death as well as more toxic chemotherapy agents that are currently used for these patients. Based on our findings related to 13-cis RA, the Children's Oncology Group has developed a national Phase III clinical trial to assess efficacy of this agent. The broad long term goals of the biology correlative studies to this clinical trial are to 1) identify biomarkers with prognostic and predictive value for future clinical trials and 2) prioritize candidate targeted therapies for future clinical trials. The specific aims of this proposal are to utilize ex vivo surgical specimens to 1) identify biomarkers predicting therapy failure in high-risk medulloblastomas/SPNETs and 2) prioritize targeted therapies for future clinical trials. The significance of this work is that it is a direct means toward replacing current pediatric brain tumor treatment modalities with more effective and less toxic alternatives.