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

描述（由申请人提供）：对DNA损伤剂的抗性是癌症患者治疗中的一个重要问题。聚（ADP-核糖）聚合酶（PARP）的活化是肿瘤避免由DNA损伤剂引起的细胞死亡（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，PARP的抑制使快速分裂的肿瘤细胞对细胞毒性剂敏感，所述细胞毒性剂诱导通常通过BER系统修复的细胞损伤。然而，如果单链DNA断裂未被修复，则它们在DNA复制时形成双链断裂（DSB）。然后通过不同的机制修复后者，称为同源重组（HR）修复。因此，功能性HR机制可以补偿PARP抑制。Karmanos癌症研究所的I期服务最近获得了国家癌症研究所（NCI）癌症治疗评估计划（CTEP）的批准，以进行新型PARP抑制剂ABT-888的I期临床试验，与单链DNA损伤剂伊立替康联合治疗晚期实体瘤患者。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特征。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损伤修复机制缺陷的肿瘤（例如乳腺癌、卵巢癌、结肠癌和肺癌）对ABT- 888和伊立替康联合治疗比伊立替康单药治疗更敏感，因为HR和单链修复（提出的对伊立替康治疗耐药的机制）都可以预防。本申请的目的是提出相关研究，以支持I期试验，使用治疗前和治疗后标本进行药效学（PD）和药物基因组学（PG）分析。为了研究所述假设，将获得血液、新鲜肿瘤活检和存档组织块，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H2 AX（3-H2 AX），这对招募修复因子到DSB位点至关重要; Rad 51，HR中必需的重组酶;肿瘤抑制蛋白BRCA 2，HR介体;和切除修复酶ERCC 1。还将评估PARP表达、拓扑异构酶I表达和p53状态。该提案的目的是试图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，以确定患者的哪些遗传特征允许ABT-888与DNA损伤剂联合治疗的最大益处。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旨在测试一种市售化疗和一种新型抗癌药物在晚期实体瘤患者中的新型组合;该申请旨在为旨在更好地了解这种疗法在癌细胞中的作用机制的研究寻求资金。如果成功的话，拟议的实验可能会指明一条道路，以确定患者谁是或多或少可能对这种疗法作出反应的测定，从而允许在未来的患者个性化治疗。

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.