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.

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