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; 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伤害剂的耐药性是癌症患者治疗的重要问题。聚（ADP-核糖）聚合酶（PARP）的激活是肿瘤避免由DNA损害剂引起的细胞死亡（凋亡）的机制之一。 PARP活性对于修复单链DNA通过碱基切除修复（BER）系统的修复至关重要。因此，PARP的抑制作用使快速分散的肿瘤细胞对细胞毒性剂的敏感性诱导通常通过BER系统修复的细胞损伤。但是，如果未修复单链DNA断裂，则它们在DNA复制后会形成双链断裂（DSB）。然后通过一种称为同源重组（HR）修复的不同机制来修复后者。因此，功能性的人力资源机制可以补偿PARP抑制。 Karmanos癌症研究所的第一阶段服务最近已获得国家癌症研究所（NCI）癌症治疗评估计划（CTEP）的批准，以对新型PARP抑制剂ABT-888进行I期临床试验，并结合单个Strand DNA DNA损伤剂Irinotecan的晚期实体瘤患者的单链DNA损伤剂。 I期临床试验的主要目的是确定药物组合的建议II期剂量，以尝试找到最佳的生物学剂量（OBD）进行PARP抑制，并确定合并治疗的安全性。 PARP抑制剂ABT-888是一种新型的研究剂，在人类中尚未进行广泛研究，从未在临床上与人类的Irinotecan结合使用。我们假设肿瘤在HR DNA破坏修复机制（例如乳腺癌，卵巢，结肠和肺癌）中有缺陷，将对ABT-888和Irinotecan和单肽Irinotecan的联合治疗更敏感，因为HR和单链修复都可以预防irinotecan to Irinotecan theraption of Irinotecan the Irinotecan papy。该应用的目的是提出相关研究以支持I期试验，使用治疗后和治疗后标本来执行药效学（PD）和药物基因组学（PG）分析。为了研究所述的假设，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。评估的生物标志物包括磷酸化的H2AX（3-H2AX），这对于募集DSB位点的修复因子至关重要。 RAD51，一种重点酶，在HR中必不可少；肿瘤抑制蛋白BRCA2，人力资源介质；和切除修复酶ERCC1。 PARP表达，拓扑异构酶I表达和p53状态也将被评估。该提案的目的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，旨在确定患者的遗传特征允许ABT-888疗法与DNA损害剂相结合获得最大的益处。公共卫生相关性：癌症是世界上死亡的主要原因，癌症患者需要更有效的治疗选择。临床试验NCI＃7977旨在测试在晚期实体瘤患者中的商业化疗和新的癌症药物的新型组合；该应用程序为旨在更好地了解癌细胞中这种疗法的作用机理的研究寻求资金。如果成功的话，提出的实验可能会指向识别对这种疗法有反应的患者的测定方法，从而允许将来对患者进行个性化治疗。