Targeted therapy in ex vivo medulloblastoma/PNET

离体髓母细胞瘤/PNET 靶向治疗

• 批准号: 7048728
• 负责人: JAMES M OLSON
• 金额: $ 22.68万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-06 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048728
• 关键词: 13 cis retinoate; Wnt gene /protein; amidohydrolases; antineoplastics; biomarker; carboplatin; cisplatin; clinical research; drug adverse effect; drug interactions; drug resistance; enzyme inhibitors; human tissue; medulloblastoma; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nervous system neoplasms; neuropathology; pediatric neoplasm /cancer; pediatric pharmacology; prognosis; sonic hedgehog gene /protein

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.

描述（由申请人提供）：髓母细胞瘤/PNET的儿童目前接受手术，放射和化学疗法的治疗。幸存者经常因这些治疗而遭受严重的长期毒性。我们的实验室已在人体髓母细胞瘤和髓母细胞瘤模型的离体样品中显示，这些模型针对包括13-钙的视黄酸（RA），环孢子胺，Notch途径抑制剂，组蛋白脱乙酰基酶抑制剂和这些患者的组合诱导髓母细胞死亡的患者以及更多的效果疗法，以及这些毒性疗法的激发度，以及这些药物疗法的激发度。根据我们与13-CIS RA相关的发现，儿童肿瘤学组已开发出一项国家III期临床试验，以评估该药物的功效。生物学相关研究与该临床试验的广泛长期目标是1）确定未来临床试验的预后和预测价值的生物标志物，以及2）优先考虑候选候选疗法以供将来的临床试验。该建议的具体目的是利用离体手术标本到1）确定在高风险髓母细胞瘤/SPNET中预测治疗失败的生物标志物，以及2）优先考虑靶向疗法以供将来的临床试验。这项工作的意义在于，它是用更有效且毒性较小的替代方法代替当前的小儿脑肿瘤治疗方式的直接手段。