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Targeted therapy in ex vivo medulloblastoma/PNET

离体髓母细胞瘤/PNET 靶向治疗

基本信息

批准号：
7321081
负责人：
JAMES M OLSON
金额：
$ 22.34万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
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/7321081
关键词：
Apoptosis Apoptotic BMP2 gene Biological Biological Markers Biology Carboplatin Carboplatin/Cisplatin Cell Death Cell Line Cells Child Childhood Childhood Brain Neoplasm Children&apos s Oncology Group Clinical Data Clinical Trials Correlative Study Cytotoxic Chemotherapy Data Development Diagnosis Disease Drug Kinetics Excision Failure Foundations Future Goals Growth Histone Deacetylase Histone Deacetylase Inhibitor Hour Human Impaired cognition Inhibitory Concentration 50 Isotretinoin Laboratories Laboratory Finding Malignant - descriptor Malignant neoplasm of brain Modality Modeling Molecular Mus Operative Surgical Procedures Pathway interactions Patients Pharmaceutical Preparations Phase III Clinical Trials Predictive Value Primary Neoplasm Radiation Radiation therapy Radiation-Sensitizing Agents Radiosensitization Radiosurgery Randomized Relapse Research Personnel Resistance Retinoids Risk Series Signal Pathway Specimen Standards of Weights and Measures Supratentorial Survivors Testing Toxic effect Translating Tretinoin Work base chemotherapy cisplatin/etoposide protocol cohort combinatorial cyclopamine drug distribution drug efficacy inhibitor/antagonist innovation medulloblastoma neoplastic cell notch protein outcome forecast pre-clinical prognostic resistance mechanism response tumor tumor growth tumor xenograft

项目摘要

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.

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。我们的实验室在体外实验中来自靶向治疗的人髓母细胞瘤和小鼠髓母细胞瘤模型的标本包括13-顺式视黄酸（RA）、环巴胺、notch途径抑制剂、组蛋白脱乙酰酶抑制剂和这些药物的组合诱导成神经管细胞瘤细胞死亡以及毒性更大的化疗药物目前用于这些患者。根据我们对13-顺式RA的研究结果，肿瘤学小组已经开发了一个国家III期临床试验，以评估这种药物的疗效。广大本临床试验的生物学相关研究的长期目标是：1）鉴定生物标志物，对未来临床试验的预后和预测价值; 2）优先考虑未来的候选靶向治疗临床试验本提案的具体目的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）优先考虑靶向未来的临床试验。这项工作的意义在于它是取代的直接手段目前的儿科脑肿瘤治疗模式，更有效，毒性更低的替代品。