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

ABT-888（一种口服 POLY 抑制剂）的 I 期研究

• 批准号: 8356743
• 负责人: SUSAN M. BLANEY
• 金额: $ 0.01万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356743
• 关键词: Adult; Alkylating Agents; Base Excision Repairs; Binding; Bioavailable; Blood - brain barrier anatomy; Bos taurus PARP protein; Central Nervous System Neoplasms; Child; Childhood; Childhood Central Nervous System Neoplasm; Childhood Medulloblastomas; Clinical Research; DNA; DNA Repair; DNA Repair Pathway; DNA Single Strand Break; DNA biosynthesis; Dose; Enzymes; Funding; Glioblastoma; Glioma; Grant; Human; Malignant Glioma; Maximum Tolerated Dose; Mus; National Center for Research Resources; Nuclear; Oral; PARP inhibition; Pathway interactions; Phase; Phase I Clinical Trials; Poly(ADP-ribose) Polymerases; Pre-Clinical Model; Principal Investigator; Proteins; Recruitment Activity; Recurrence; Research; Research Infrastructure; Resistance; Resources; Solid Neoplasm; Source; United States National Institutes of Health; Xenograft procedure; chemotherapy; cost; cytotoxicity; improved; inhibitor/antagonist; medulloblastoma; phase 1 study; preclinical study; repaired; response; temozolomide; tumor

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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 替莫唑胺 (TMZ) 是一种口服烷化剂，对复发性儿童中枢神经系统肿瘤（包括高级别神经胶质瘤、髓母细胞瘤/PNET 和低级别神经胶质瘤）显示出一定的活性。鉴于替莫唑胺的客观缓解率较低（20%），大多数儿童中枢神经系统肿瘤可能对替莫唑胺或其他烷化剂具有新的或获得性耐药性。替莫唑胺会诱导单链 DNA 断裂，其中大部分通过碱基切除修复 (BER) 途径进行修复。聚 (ADP-核糖) 聚合酶 (PARP) 是一种关键的核酶，可与 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、停止 DNA 复制并促进受损 DNA 的修复。在儿科恶性神经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，这代表了肿瘤对烷化剂产生耐药性的可能机制。临床前研究表明，PARP 抑制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可利用的 PARP 抑制剂，在多种人类肿瘤临床前模型中已被证明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 可有效穿过血脑屏障，优先在小鼠小儿髓母细胞瘤和多形性胶质母细胞瘤的颅内异种移植物中积累，有效抑制 PARP 活性和其他 DNA 修复途径，并改善肿瘤对替莫唑胺的反应。 ABT-888和替莫唑胺在成人复发/进行性实体瘤中的1期临床试验已完成，ABT-888和替莫唑胺的推荐2期剂量分别为40 mg bid和200 mg/m2/day x 5天，每28天一次。在这项 1 期试验中，我们将估计 ABT-888 和替莫唑胺联合治疗复发/进行性中枢神经系统肿瘤儿童的最大耐受剂量 (MTD) 或推荐 2 期剂量。