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）：患有髓母细胞瘤/PNET 的儿童目前接受手术、放疗和化疗治疗。幸存者常常因这些治疗而遭受严重的长期毒性。我们的实验室在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)、环巴明、Notch 通路抑制剂、组蛋白脱乙酰酶抑制剂以及这些药物的组合可诱导髓母细胞瘤细胞死亡等目前用于这些患者的有毒化疗药物。根据我们与 13-cis RA 相关的研究结果，儿童肿瘤学组开发了一项国家 III 期临床试验来评估该药物的疗效。该临床试验的生物学相关研究的广泛长期目标是：1）识别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疗法。该提案的具体目标是利用离体手术标本 1) 识别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，它是用更有效、毒性更小的替代方案取代当前的儿科脑肿瘤治疗方式的直接方法。