Study of Valproic Acid in Pediatric Brain Tumors

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中寻找新的治疗方法，并开发生物驱动的、机制特定的临床试验。他目前的重点是研究丙戊酸和其他相关的组蛋白脱乙酰酶(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小组对患有复发的实体和中枢神经系统肿瘤的儿童进行丙戊酸的一期临床试验。这项第一阶段临床试验的主要目标是记录长期服用丙戊酸对复发肿瘤儿童的毒性和药代动力学，并确定血清药物浓度与组蛋白超乙酰化之间的相关性，组蛋白超乙酰化是被提出的抗肿瘤机制。苏博士已经完成了随后的第二阶段临床试验的提案，以研究丙戊酸对复发的儿童中枢神经系统肿瘤的疗效，该提案将在正在进行的第一阶段临床试验完成后提交给一个国家合作小组。苏博士和他的合作者还展示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最小残留肿瘤方面的潜力。因此，苏博士计划启动一项一期临床试验，研究在新诊断为MBS的儿童中同时使用丙戊酸和放射治疗的安全性。如果他的初步临床试验表明丙戊酸对MBS有很好的治疗效果，苏博士将探索进行全国性合作小组第三阶段试验的可能性，在该试验中，患者接受丙戊酸的预先放射治疗、完全化疗，然后随机进行观察，与丙戊酸进行为期一年的观察。苏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，毒性更低。另一项临床前研究计划评估替莫唑胺和一种聚(ADP-核糖)聚合酶(PARP)抑制剂对儿童恶性胶质瘤和MBS的联合疗效。总而言之，苏医生在将分子发现转化为临床试验方面表现出了早期的希望，他致力于作为儿科神经肿瘤学的独立临床研究员的职业发展。

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.