A PHASE I STUDY OF ABT-888, AN ORAL INHIBITOR OF POLY

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 替莫唑胺(TMZ)是一种口服烷化剂，在儿童复发性中枢神经系统肿瘤中显示出适度的活性，包括高级别胶质瘤、髓母细胞瘤/PNET和低级别胶质瘤。考虑到替莫唑胺的客观有效率很低(20%)，很可能大多数儿童中枢神经系统肿瘤对替莫唑胺或其他烷化剂具有新生或获得性耐药。替莫唑胺诱导单链DNA断裂，其中大部分通过碱基切除修复(BER)途径修复。多聚(ADP-核糖)聚合酶，或PARP，是一种关键的核酶，它与DNA断裂结合，招募并激活BER和其他DNA修复途径中的关键蛋白，阻止DNA复制，促进DNA损伤的修复。在儿童恶性胶质瘤和髓母细胞瘤中检测到高水平的PARP蛋白和/或酶活性，这可能是肿瘤对烷基化药物耐药的机制之一。临床前研究表明，抑制PARP可增强恶性胶质瘤对替莫唑胺的敏感性。ABT-888是一种有效的口服生物利用的PARP抑制剂，已被证明在几种人类肿瘤的临床前模型中可以增强替莫唑胺和其他化疗药物的细胞毒性。我们已经证明ABT-888有效地跨越血脑屏障，在儿童髓母细胞瘤和多形性胶质母细胞瘤的颅内移植瘤中优先蓄积，有效地抑制PARP活性和其他DNA修复途径，并提高肿瘤对替莫唑胺的反应。ABT-888和替莫唑胺的1期临床试验已经在成人复发/进展期实体肿瘤患者中完成，推荐的2期剂量分别为40 mg bid和200 mg/m2/d×5天，每28天一次。在这项第一阶段试验中，我们将评估ABT-888和替莫唑胺联合治疗复发/进展的儿童中枢神经系统肿瘤的最大耐受剂量(MTD)或推荐第二阶段剂量。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Temozolomide (TMZ), an oral alkylating agent, has shown modest activity in recurrent pediatric CNS tumors, including high-grade gliomas, medulloblastoma/PNET, and low-grade gliomas. Given the low rate of objective response to temozolomide ( 20%), it is probable that most pediatric CNS tumors have de novo or acquired resistance to temozolomide or other alkylating agents. Temozolomide induces single-stranded DNA breaks, the majority of which are repaired by the base excision repair (BER) pathway. Poly(ADP-ribose) polymerase, or PARP, is a critical nuclear enzyme that binds to DNA breaks, recruits and activates key proteins in the BER and other DNA repair pathways, halts DNA replication, and facilitates repair of damaged DNA. High levels of PARP proteins and/or enzymatic activity have been detected in pediatric malignant gliomas and medulloblastomas and represent a likely mechanism of tumor resistance to alkylating agents. Pre-clinical studies have shown that PARP inhibition enhances the sensitivity of malignant gliomas to temozolomide. ABT-888 is a potent and orally bioavailable PARP inhibitor that has been shown to enhance cytotoxicity of temozolomide and other chemotherapy agents in several pre-clinical models of human tumors. We have demonstrated that ABT-888 crosses the blood-brain barrier effectively, accumulates preferentially in intracranial xenografts of pediatric medulloblastoma and glioblastoma multiforme in mice, potently inhibits PARP activity and other DNA repair pathways, and improves tumor response to temozolomide. Phase 1 clinical trials of ABT-888 and temozolomide have been completed in adults with recurrent/progressive solid tumors, and the recommended phase 2 doses of ABT-888 and temozolomide are 40 mg bid and 200 mg/m2/day x 5 days every 28 days respectively. In this phase 1 trial we will estimate the maximum tolerated dose (MTD) or recommend Phase 2 doses of the combination of ABT-888 and temozolomide in children with recurrent/progressive CNS tumors.