Targeted therapy in ex vivo medulloblastoma/PNET

患有髓母细胞瘤/PNET的儿童目前正在接受手术、放疗和化疗。 幸存者往往因这些治疗而遭受严重的长期毒性。我们的实验室已经在体外显示了 靶向治疗的人髓母细胞瘤和小鼠髓母细胞瘤模型标本 包括13-顺式维甲酸(RA)、环胺、Noch途径抑制剂、组蛋白脱乙酰酶抑制剂和 这些药物的组合会导致髓母细胞瘤细胞死亡以及更多有毒的化疗药物 目前用于这些患者的药物。根据我们对13-cis RA的研究结果，儿童的 肿瘤学小组已经开发了一项国家第三阶段临床试验，以评估该药物的疗效。《博大》 与这项临床试验相关的生物学研究的长期目标是：1)识别生物标志物 对未来临床试验的预后和预测价值以及2)未来候选靶向治疗的优先顺序 临床试验。这项提议的具体目的是利用体外手术标本来识别 预测高危髓母细胞瘤/SPNET治疗失败的生物标志物和2)优先靶向 未来临床试验的治疗方法。这项工作的意义在于它是一种直接的手段 目前儿科脑肿瘤的治疗方式有更有效和毒性更低的替代方案。

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.