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

描述(由申请人提供)：对DNA损伤剂的抗药性是癌症患者治疗中的一个重大问题。聚腺苷二磷酸核糖聚合酶(PARP)的激活是肿瘤避免DNA损伤剂引起的细胞死亡(凋亡)的机制之一。PARP活性是通过碱基切除修复(BER)系统修复单链DNA断裂所必需的。因此，抑制PARP使快速分裂的肿瘤细胞对细胞毒剂敏感，这些毒剂导致通常通过BER系统修复的细胞损伤。然而，如果单链DNA断裂得不到修复，它们就会在DNA复制时形成双链断裂(DSB)。后者然后通过一种不同的机制修复，称为同源重组(HR)修复。因此，一个正常运作的HR机制可能会补偿PARP抑制。卡马诺斯癌症研究所的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，将进行新型PARP抑制剂ABT-888与单链DNA损伤剂伊立替康联合用于晚期实体肿瘤患者的I期临床试验。I期临床试验的主要目的是确定该药物组合的推荐II期剂量，试图找到抑制PARP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是一种新的研究药物，尚未在人体内广泛研究，也从未在临床上与伊立替康联合应用。我们假设，HR DNA损伤修复机制缺陷的肿瘤(如乳腺癌、卵巢癌、结肠癌和肺癌)对ABT-888和伊立替康的联合治疗比伊立替康单一治疗更敏感，因为HR和单链修复，这两种已提出的抵抗伊立替康治疗的机制，都可能被预防。本申请的目的是提出支持第一阶段试验的相关研究，使用治疗前和治疗后的样本进行药效学(PD)和药物基因组学(PG)分析。为了验证上述假设，将获得血液、新鲜肿瘤活检组织和档案组织块，以帮助确定参与DSB修复的重要候选生物标记物蛋白的表达水平、突变状态或多态。正在评估的生物标记物包括磷酸化的H_2AX(3-H_2AX)，它是将修复因子招募到DSB位点的关键；RAD51，HR中必不可少的重组酶；肿瘤抑制蛋白BRCA2，HR的介体；以及切除修复酶ERCC1。还将评估PARP表达、拓扑异构酶I表达和P53状态。这项提案的目标是试图确定一组生物标记物，这些生物标记物将在未来的研究中进行检查，以确定哪些患者的遗传特征可以从ABT-888疗法与DNA损伤剂的结合中获得最大好处。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。NCI#7977临床试验旨在测试一种商业上可用的化疗和一种新型抗癌药物在晚期实体肿瘤患者中的新组合；这项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，拟议中的实验可能会为识别或多或少对这种疗法有反应的患者指明方向，从而允许未来对患者进行个性化治疗。

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.