Study of Valproic Acid in Pediatric Brain Tumors

丙戊酸治疗小儿脑肿瘤的研究

• 批准号: 7147565
• 负责人: JACK Meng Fen SU
• 金额: $ 13.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147565
• 关键词: acetylation; brain; children; clinical research; clinical trials; histones; neoplasm /cancer; serum

DESCRIPTION (provided by applicant): Dr. Su's long-term career objectives are to identify novel treatments and develop biology-driven, mechanism-specific clinical trials in pediatric neuro-oncology. His current focus is on studying valproic acid and other related histone deacetylase (HDAC) inhibitors as novel treatments for medulloblastomas (MB). Based on his pre-clinical studies, Dr. Su is currently conducting a Phase 1 clinical trial of valproic acid in children with recurrent solid and CNS tumors through the Children's Oncology Group. The major goals of this Phase 1 clinical trial are to document the toxicities and pharmacokinetics of chronic valproic acid administration in children with recurrent tumors and determine the correlation between serum drug concentrations and histone hyper-acetylation, the proposed anti-tumor mechanism. Dr. Su has completed a proposal for a subsequent Phase 2 clinical trial to study valproic acid's efficacy against recurrent pediatric CNS tumors, and this proposal will be submitted to a national cooperative group upon completion of the ongoing Phase 1 clinical trial. Dr. Su and his collaborators have also demonstrated valproic acid's potential in protecting normal brain against radiation-damage, enhancing MBs' radiation sensitivity, and treating minimal residual tumors. Accordingly, Dr. Su plans to initiate a Phase 1 clinical trial to study the safety of administering valproic acid concomitantly with radiation in children newly diagnosed with MBs. If his initial clinical trials showed that valproic acid has promising activities against MBs, Dr. Su will explore the potential for a national cooperative group Phase 3 trial, in which patients receive valproic acid with up-front radiation, complete chemotherapy, and then are randomized to observation versus valproic acid for a year. Dr. Su and his collaborators also plan to evaluate additional HDAC inhibitors, as they may be more potent and less toxic than valproic acid. Another pre-clinical study is planned to evaluate the combined efficacies of temozolomide and a poly (ADP- ribose) polymerase (PARP) inhibitor against pediatric malignant gliomas and MBs. In summary, Dr. Su's has demonstrated early promise in translating molecular discoveries into clinical trials, and he is committed to his career development as an independent clinical researcher in pediatric neuro-oncology.

描述（由申请人提供）：苏博士的长期职业目标是在儿科神经肿瘤学领域寻找新的治疗方法并开发生物学驱动的、机制特异性的临床试验。他目前的重点是研究丙戊酸和其他相关组蛋白脱乙酰酶 (HDAC) 抑制剂作为髓母细胞瘤 (MB) 的新疗法。基于他的临床前研究，苏博士目前正在通过儿童肿瘤学组对患有复发性实体瘤和中枢神经系统肿瘤的儿童进行丙戊酸的一期临床试验。该一期临床试验的主要目标是记录复发性肿瘤儿童长期服用丙戊酸的毒性和药代动力学，并确定血清药物浓度与组蛋白过度乙酰化（拟议的抗肿瘤机制）之间的相关性。苏博士已完成后续二期临床试验的提案，以研究丙戊酸对复发性儿童中枢神经系统肿瘤的疗效，该提案将在正在进行的一期临床试验完成后提交给国家合作组。苏博士和他的合作者还证明了丙戊酸在保护正常大脑免受辐射损伤、增强MBs的辐射敏感性以及治疗微小残留肿瘤方面的潜力。因此，苏博士计划启动一项 1 期临床试验，以研究在新诊断患有 MB 的儿童中给予丙戊酸并同时进行放射治疗的安全性。如果他的初步临床试验表明丙戊酸对 MBs 具有良好的活性，苏博士将探索国家合作组 3 期试验的潜力，其中患者接受丙戊酸并进行前期放疗，完成化疗，然后随机观察一年，与丙戊酸进行对比。 Su 博士和他的合作者还计划评估其他 HDAC 抑制剂，因为它们可能比丙戊酸更有效且毒性更小。另一项临床前研究计划评估替莫唑胺和聚（ADP-核糖）聚合酶（PARP）抑制剂对儿童恶性胶质瘤和 MB 的联合疗效。总之，苏博士在将分子发现转化为临床试验方面表现出了早期的希望，并且他致力于作为儿科神经肿瘤学独立临床研究员的职业发展。