Targeted therapy in ex vivo medulloblastoma/PNET

描述（由申请人提供）： 患有髓母细胞瘤/PNET的儿童目前接受手术、放疗和化疗。幸存者往往遭受严重的长期毒性，从这些治疗。我们的实验室已经在来自人髓母细胞瘤和小鼠髓母细胞瘤模型的离体标本中显示，靶向治疗包括13-顺式视黄酸（RA）、环巴胺、notch通路抑制剂、组蛋白脱乙酰酶抑制剂和这些药物的组合诱导髓母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-顺式RA相关的发现，儿童肿瘤组已经开发了一项国家III期临床试验，以评估该药物的疗效。本临床试验的生物学相关研究的广泛长期目标是：1）确定对未来临床试验具有预后和预测价值的生物标志物，2）优先考虑未来临床试验的候选靶向治疗。本提案的具体目的是利用离体手术标本1）确定预测高危髓母细胞瘤/SPNET治疗失败的生物标志物，2）优先考虑未来临床试验的靶向治疗。这项工作的意义在于，它是一种直接的手段，可以用更有效、毒性更低的替代品取代目前的儿科脑肿瘤治疗方式。

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.