Mechanism-Based Use of Chk1 Inhibitors in Pancreas Cancer

基于机制的 Chk1 抑制剂在胰腺癌中的应用

• 批准号: 7891047
• 负责人: THEODORE S LAWRENCE
• 金额: $ 41.39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891047
• 关键词: Abbreviations; Address; Affect; Biological; Biological Assay; Biological Markers; Biopsy; Cancer Patient; Cause of Death; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Line; Cell Survival; Chemosensitization; Cisplatin; Clinical Research; Clinical Trials; Consensus; Cytotoxic agent; DNA Damage; DNA Repair; Data; Diagnosis; Disease; Disease-Free Survival; Dose; Dose-Limiting; Drug Delivery Systems; Drug usage; Event; Exhibits; Failure; Fluorouracil; Future; Goals; Gray unit of radiation dose; Human; Implant; In Vitro; Intensity-Modulated Radiotherapy; Laboratory Study; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Methods; Modeling; Molecular; Motivation; Nonhomologous DNA End Joining; Normal tissue morphology; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase III Clinical Trials; Phosphorylation; Play; Proteins; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Randomized; Relative (related person); Research; Resistance; Role; Sampling; Schedule; Skin; Systemic Therapy; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Toxic effect; Treatment Effectiveness; Tumor Cell Line; Unresectable; Work; Xenograft Model; Xenograft procedure; advanced disease; base; chemosensitizing agent; chemotherapy; cytotoxic; design; established cell line; gemcitabine; homologous recombination; improved; in vivo; inhibitor/antagonist; insight; interest; mortality; neoplastic cell; new therapeutic target; novel; oxaliplatin; pancreatic neoplasm; pre-clinical; preclinical study; public health relevance; recombinational repair; rectal; standard care; tumor; tumor xenograft

DESCRIPTION (provided by applicant): A strategy showing great promise for treating pancreatic cancer is to combine cytotoxic treatments with agents that abrogate the already-tenuous checkpoint functionality exhibited by most tumor cells. Drugs that target the checkpoint protein Chk1 (such as AZD7762, currently in Phase-I clinical trials) are of particular interest in the context of pancreatic cancer because Chk1 has also been shown to have a critical role in mediating the activity of Rad51, a key protein in homologous recombination repair (HRR) that is associated with resistance to DNA damaging treatments, and is upregulate in human pancreatic tumors. The long-term goal of our work is to improve the outcome of patients with pancreatic cancer by rationally adding Chk1 inhibitors to the combination of gemcitabine (Gem) + radiation. Our preliminary data show that AZD7762 is a potent chemo- and radiosensitizer of human pancreatic tumor cell lines that both decreases HRR and abrogates the G2/M checkpoint. Specific Aim 1 is to determine the relative roles of cell cycle checkpoint abrogation and HRR inhibition in chemo- and radiosensitization by AZD7762. This work will allow us to identify mechanism-based molecular endpoints to be interrogated in future clinical studies, and to identify new targets for therapeutic intervention related to HRR activity. We hypothesize that checkpoint abrogation and HRR inhibition each play key but differing roles in (to Gem) and by AZD7762. Our preliminary results using both established cell lines implanted as xenografts and early passage human tumor xenografts also show that AZD7762 is a potent chemo- and radiosensitizer in vivo, providing strong motivation for conducting a clinical trial. Specific Aim 2 is to use xenograft models to establish the basis for conducting a clinical trial combining AZD7762 with Gem + radiation, evaluating the role of drug schedule. The results of Aim 2 will help to define the design of our subsequent clinical trial. Specific Aim 3 is to carry out a clinical trial using AZD7762 in combination with Gem + radiation in patients with locally advanced, unresectable pancreatic cancer. We will use a combination of Gem + radiation followed by Gem alone, combined with dose-escalating AZD7762, based on the schedule suggested in Aim 2. We hypothesize that the MTD for AZD7762 will be similar to that determined in the current phase I trials using Gem alone (i.e. that adding conformal radiation will have a minimal impact on the MTD of AZD7762 in combination with Gem). Also, we hypothesize that AZD7762 will inhibit Chk1 activity in surrogate normal tissues when administered at the MTD, and, possibly, at lower doses. PUBLIC HEALTH RELEVANCE: This project is directly aimed at improving treatment of patients with pancreatic cancer, by identifying the biological differences among human pancreatic tumors that determine how well patients respond when a new type of drug ("checkpoint inhibitor") is added to the current standard treatment for this disease (Gemcitabine plus radiation). The research plan includes both a clinical trial for patients diagnosed with unresectable (inoperable) pancreatic cancer, and laboratory studies using well-studied cell lines derived from pancreatic cancer patients.

描述（由申请人提供）：一种显示出治疗胰腺癌的巨大前景的策略是将细胞毒性治疗与消除大多数肿瘤细胞所表现出的已经脆弱的检查点功能的药剂组合联合收割机。靶向检查点蛋白Chk 1的药物（例如目前处于I期临床试验的AZD 7762）在胰腺癌的背景下特别令人感兴趣，因为Chk 1也已被证明在介导Rad 51的活性方面具有关键作用，Rad 51是同源重组修复（HRR）中的关键蛋白，与DNA损伤治疗的抗性相关，并且在人类胰腺肿瘤中上调。我们工作的长期目标是通过在吉西他滨（Gem）+放疗的联合方案中合理添加Chk 1抑制剂来改善胰腺癌患者的预后。我们的初步数据表明，AZD 7762是一种有效的化疗和放射增敏剂的人胰腺肿瘤细胞系，既降低HRR和废除G2/M检查点。具体目标1是确定细胞周期检查点废除和HRR抑制在AZD 7762的化疗和放射增敏中的相对作用。这项工作将使我们能够确定在未来的临床研究中要询问的基于机制的分子终点，并确定与HRR活性相关的治疗干预的新靶点。我们假设检查点废除和HRR抑制各自在（对Gem）和AZD 7762中发挥关键但不同的作用。我们使用已建立的细胞系作为异种移植物和早期传代人肿瘤异种移植物植入的初步结果也表明，AZD 7762是一种有效的体内化疗和放射增敏剂，为进行临床试验提供了强大的动力。具体目标2是使用异种移植模型为进行AZD 7762与Gem +辐射联合的临床试验奠定基础，以评估药物方案的作用。目标2的结果将有助于确定我们后续临床试验的设计。具体目标3是在局部晚期、不可切除的胰腺癌患者中开展AZD 7762联合Gem +放疗的临床试验。我们将根据目标2中建议的时间表，联合使用Gem +辐射，然后单独使用Gem，并联合剂量递增的AZD 7762。我们假设AZD 7762的MTD将与当前I期试验中单独使用Gem确定的MTD相似（即，增加适形放疗对AZD 7762联合Gem的MTD影响最小）。此外，我们假设AZD 7762以MTD给药时，以及可能以较低剂量给药时，会抑制替代正常组织中的Chk 1活性。 公共卫生关系：该项目的直接目的是通过确定人类胰腺肿瘤之间的生物学差异来改善胰腺癌患者的治疗，这些生物学差异决定了当新型药物（“检查点抑制剂”）添加到该疾病的当前标准治疗（吉西他滨加放射）时患者的反应如何。该研究计划包括对诊断为不可切除（不可手术）的胰腺癌患者进行临床试验，以及使用来自胰腺癌患者的经过充分研究的细胞系进行实验室研究。