GENETICS OF CHILDHOOD SOLID TUMORS

儿童实体瘤的遗传学

• 批准号: 5207006
• 负责人: A THOMAS LOOK
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5207006
• 关键词: Ewing's tumor; brain neoplasms; cancer information system; cell cycle; cell cycle proteins; cell growth regulation; child (0-11); clone cells; cytogenetics; flow cytometry; gel electrophoresis; gene mutation; glioma; human subject; in situ hybridization; longitudinal human study; medulloblastoma; natural gene amplification; neoplasm /cancer epidemiology; neoplasm /cancer genetics; neoplastic cell; neuroblastoma; nucleic acid sequence; oncogenes; osteosarcoma; pediatric neoplasm /cancer; point mutation; polymerase chain reaction; radiation carcinogenesis; radiation dosage; rhabdomyosarcoma; sarcoma

This research combines three approaches - genetic analysis of tumor cells, pharmacokinetic studies and phase I, II and II-III pilot trials - to improve the curability of childhood sarcomas that have proved resistant to conventional therapy. Project 7A will seek to identify consistent molecular and genetic abnormalities in each of the three sarcomas under study (rhabdomyosarcoma, Ewing sarcoma and osteosarcoma) and determine their clinical significance through careful correlation with clinicopathologic staging and therapeutic response. Project 7B will concentrate on (i) the pharmacokinetics of antineoplastic drugs in children and the clinical factors that influence such parameters, (ii) drug concentration-effect relationships in children (pharmacodynamics), and (iii) correlations between pharmacokinetic/pharmacodynamic findings in mouse xenograft systems and cancer patients, to improve the "scale-up" from experimental models to clinical evaluation. Finally, the series of clinical trials described in this section will serve as the primary means of testing agents and concepts emerging from Projects 1-6, 7A and 7B, and from other sources such as the NCI. Phase I and II trials (Project 7C) will be conducted in a conventional manner except that maximum use will be made of pharmacokinetic data to refine drug scheduling and dose modification. In Project 7D, we will use an innovative strategy to circumvent a persistent problem in drug development: missing the potential activity of a compound because of its poor performance in phase II trials with heavily pretreated patients. Hence, agents and concepts that appear worthy of continued testing will be investigated in previously untreated patients with a poor prognosis prior to the start of more established therapy (phase II-III pilot studies). We anticipate that the interactive nature of these efforts will result in a more productive developmental therapeutics program in the solid tumors of childhood, one that should generate provocative leads for analysis in randomized clinical trials within the national cooperative groups.

这项研究结合了三种方法 - 遗传分析 肿瘤细胞，药代动力学研究以及I期，II和II-III驾驶 试验 - 提高具有儿童肉瘤的可固化性 事实证明对常规疗法有抵抗力。 项目7A将寻求 识别每一个一致的分​​子和遗传异常 研究的三个肉瘤（横纹肌肉瘤，尤因 肉瘤和骨肉瘤）并确定其临床 通过与临床病理学的仔细关联来显着性 分期和治疗反应。 项目7B将集中于 （i）儿童抗肿瘤药物的药代动力学和 影响此参数的临床因素，（ii）药物 儿童的集中效应关系 （药效学）和（iii）之间的相关性 小鼠异种移植物中的药代动力学/药效学发现 系统和癌症患者，以改善从 实验模型进行临床评估。 最后，系列 本节中描述的临床试验将作为主要 测试从项目1-6出现的代理和概念的方法， 7a和7b，以及其他来源，例如NCI。 第一阶段和第二阶段 试验（项目7C）将以传统的方式进行 除了最大使用药代动力学数据 完善药物调度和剂量修改。 在项目7D中 我们将使用创新策略来规避持久性 药物开发问题：缺少A的潜在活性 由于在II期试验中的性能较差，因此具有 大量预处理患者。 因此，代理和概念 似乎值得继续进行测试 以前未经治疗的患者在预后较差 开始更既定的疗法（II-III期试点研究）。 我们 预计这些努力的互动性质将导致 在一项更有生产力的发育治疗计划中 童年的实体瘤，应该产生挑衅性 在国家内的随机临床试验中进行分析的铅 合作团体。