Correlative Studies for NCI Study #7977: Phase I trial of ABT-888 Plus Irinotecan

NCI研究的相关研究

• 批准号: 7525941
• 负责人: PATRICIA M. LORUSSO
• 金额: $ 35.08万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7525941
• 关键词: Antineoplastic Agents; Apoptosis; Applications Grants; BRCA1 gene; BRCA2 gene; Base Excision Repairs; Biological Assay; Biological Markers; Biological Models; Biopsy; Blood; Breast; Cancer Center; Cancer Patient; Cancer Therapy Evaluation Program; Cause of Death; Cell Death; Cell Line; Characteristics; Clinical; Clinical Trials; Colon; Combined Modality Therapy; Correlative Study; Cytochrome P450; Cytotoxic agent; DNA Damage; DNA Repair; DNA Repair Gene; DNA Single Strand Break; DNA biosynthesis; Defect; Dose; Double Strand Break Repair; Drug Combinations; Drug Kinetics; ERCC1 gene; End Point; Enzymes; Evaluation; Excision; Funding; Future; Genetic; Genetic Polymorphism; Genus Cola; Goals; H2AFX gene; Human; Institutes; Malignant Neoplasms; Malignant neoplasm of lung; Maryland; Measures; Mediator of activation protein; Messenger RNA; Metabolism; Mutation; National Cancer Institute; Outcome; Ovarian; PARP inhibition; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Phase; Phase I Clinical Trials; Poly(ADP-ribose) Polymerases; Pre-Clinical Model; Proteins; Public Health; Purpose; Recruitment Activity; Research Design; Resistance; Safety; Sampling; Services; Site; Solid Neoplasm; Specimen; Standards of Weights and Measures; System; TP53 gene; Testing; Tissues; Toxic effect; Treatment Protocols; Tumor Suppressor Proteins; Tumor Tissue; Type I DNA Topoisomerases; United States National Institutes of Health; Universities; Unresectable; base; cancer cell; cell injury; chemotherapy; clinically relevant; design; ds-DNA; genetic variant; genetically modified cells; homologous recombination; human H2AX protein; human TOP1 protein; inhibitor/antagonist; irinotecan; mutant; neoplastic cell; novel; prevent; recombinase; recombinational repair; repair enzyme; repaired; research study; resistance mechanism; response; tumor

DESCRIPTION (provided by applicant): Resistance to DNA-damaging agents is a significant problem in the treatment of cancer patients. Activation of poly(ADP-ribose) polymerase (PARP) is one of the mechanisms by which tumors avoid cell death (apoptosis) caused by DNA-damaging agents. PARP activity is essential for the repair of single-stranded DNA breaks through the base excision repair (BER) system. Therefore, inhibition of PARP sensitizes rapidly-dividing tumor cells to cytotoxic agents which induce cell damage normally repaired through the BER system. However, if single strand DNA breaks are not repaired, they form double strand breaks (DSB) upon DNA replication. The latter are then repaired through a different mechanism, called homologous recombination (HR) repair. A functioning HR mechanism may, therefore, compensate for PARP inhibition. The Karmanos Cancer Institute's Phase I service has recently received approval from the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) to conduct a Phase I clinical trial of the novel PARP inhibitor ABT-888, in combination with the single strand DNA-damaging agent irinotecan in patients with advanced solid tumors. The primary aim of the Phase I clinical trial is to determine the recommended Phase II dose of the drug combination, to attempt to find the optimal biologic dose (OBD) for PARP inhibition, and to determine the safety profile of the combined therapy. The PARP inhibitor ABT-888 is a novel investigational agent that has not been extensively studied in humans, and never clinically in combination with irinotecan in humans. We hypothesize that tumors defective in HR DNA-damage repair mechanisms (e.g. breast, ovarian, colon and lung cancer), will be more sensitive to the combination therapy of ABT- 888 and irinotecan versus monotherapy irinotecan because both HR and single strand repair, proposed mechanisms of resistance to irinotecan therapy, may be prevented. The purpose of this application is to propose correlative studies in support of the Phase I trial, using pre- and post-treatment specimens to perform pharmacodynamic (PD) and pharmacogenomic (PG) analyses. To investigate the stated hypothesis, blood, fresh tumor biopsies, and archival tissue blocks will be obtained to assist in determining expression levels, mutation status, or polymorphisms of important candidate biomarker proteins involved in DSB repair. Biomarkers under evaluation include phosphorylated H2AX (3-H2AX), which is critical to recruit repair factors to DSB sites; Rad51, a recombinase essential in HR; the tumor suppressor protein BRCA2, a HR mediator; and the excision repair enzyme ERCC1. PARP expression, topoisomerase I expression, and p53 status will also be assessed. The goal of this proposal is to attempt to identify a set of biomarkers that will be examined in future studies designed to determine which genetic characteristics of patients allow for the greatest benefit from ABT-888 therapy in combination with DNA damaging agents. PUBLIC HEALTH RELEVANCE: Cancer is a major cause of death in the world and cancer patients are in need of more effective treatment options. The clinical trial NCI#7977 is designed to test a novel combination of a commercially-available chemotherapy and a new cancer drug in patients with advanced solid tumors; this application seeks funding for studies designed to better understand the mechanism of action of this therapy in cancer cells. If successful, the proposed experiments may point the way to assays that identify patients who are more or less likely to respond to this therapy, thereby permitting individualized therapy of patients in the future.

描述（由申请人提供）：对 DNA 损伤剂的耐药性是癌症患者治疗中的一个重要问题。聚（ADP-核糖）聚合酶（PARP）的激活是肿瘤避免 DNA 损伤剂引起的细胞死亡（细胞凋亡）的机制之一。 PARP 活性对于通过碱基切除修复 (BER) 系统修复单链 DNA 断裂至关重要。因此，抑制 PARP 会使快速分裂的肿瘤细胞对细胞毒性药物敏感，从而诱导通常通过 BER 系统修复的细胞损伤。然而，如果单链 DNA 断裂没有得到修复，它们就会在 DNA 复制时形成双链断裂 (DSB)。然后，后者通过不同的机制进行修复，称为同源重组（HR）修复。因此，有效的 HR 机制可以补偿 PARP 抑制。 Karmanos 癌症研究所的 I 期服务最近获得了美国国家癌症研究所 (NCI) 癌症治疗评估计划 (CTEP) 的批准，可对新型 PARP 抑制剂 ABT-888 与单链 DNA 结合进行 I 期临床试验。晚期实体瘤患者的损伤剂伊立替康。 I期临床试验的主要目的是确定药物组合的推荐II期剂量，试图找到PARP抑制的最佳生物剂量（OBD），并确定联合治疗的安全性。 PARP 抑制剂 ABT-888 是一种新型研究药物，尚未在人体中进行广泛研究，也从未在临床上与伊立替康联合用于人体。我们假设 HR DNA 损伤修复机制有缺陷的肿瘤（例如乳腺癌、卵巢癌、结肠癌和肺癌），与伊立替康单药治疗相比，对 ABT-888 和伊立替康联合治疗更敏感，因为 HR 和单链修复都被提出。伊立替康治疗的耐药机制是可以预防的。本申请的目的是提出支持 I 期试验的相关研究，使用治疗前和治疗后样本进行药效学 (PD) 和药物基因组学 (PG) 分析。为了研究所述假设，将获得血液、新鲜肿瘤活检和档案组织块，以帮助确定参与 DSB 修复的重要候选生物标志物蛋白的表达水平、突变状态或多态性。正在评估的生物标志物包括磷酸化 H2AX (3-H2AX)，它对于向 DSB 位点募集修复因子至关重要； Rad51，HR 中必需的重组酶；肿瘤抑制蛋白 BRCA2，HR 介质；和切除修复酶 ERCC1。还将评估 PARP 表达、拓扑异构酶 I 表达和 p53 状态。该提案的目标是尝试确定一组生物标志物，这些生物标志物将在未来的研究中进行检查，旨在确定患者的哪些遗传特征可以从 ABT-888 与 DNA 损伤剂联合治疗中获得最大益处。公共卫生相关性：癌症是世界上主要的死亡原因，癌症患者需要更有效的治疗选择。临床试验 NCI#7977 旨在测试一种商业化化疗和一种新抗癌药物的新型组合，用于治疗晚期实体瘤患者；该申请寻求资助旨在更好地了解这种疗法在癌细胞中的作用机制的研究。如果成功，所提出的实验可能会为确定哪些患者或多或少可能对该疗法产生反应的检测指明道路，从而允许未来对患者进行个体化治疗。