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

基本信息

批准号：
8242063
负责人：
THEODORE S LAWRENCE
金额：
$ 44.01万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/8242063
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 recombinational repair rectal standard care tumor tumor xenograft

项目摘要

PROJECT ABSTRACT 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 upregulated 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.

项目摘要一种表现出治疗胰腺癌的巨大希望的策略是将细胞毒性治疗与剂相结合这消除了大多数肿瘤细胞所表现出的本来就很繁琐的检查点功能。针对目标的药物检查点蛋白CHK1（例如AZD7762，目前正在I期临床试验中）特别关注胰腺癌的背景是因为CHK1也已被证明在介导活动中起着至关重要的作用 Rad51（同源重组修复（HRR）中的关键蛋白质，与DNA抗性有关损害治疗方法，并在人类胰腺肿瘤中上调。我们工作的长期目标是通过合理地将CHK1抑制剂添加到吉西他滨（GEM） +辐射的组合。我们的初步数据表明，AZD7762是一种有效的化学疗法人类胰腺肿瘤细胞系的放射敏剂均降低HRR并消除G2/M 检查点。具体目的1是确定细胞周期检查点废除和 AZD7762在化学和放射敏化中的HRR抑制作用。这项工作将使我们能够确定基于机理的分子终点将在未来的临床研究中询问，并确定新目标用于与HRR活性有关的治疗干预措施。我们假设该检查点废除和HRR 抑制每个弹奏键，但在（宝石）和AZD7762中的角色不同。我们使用两者的初步结果已植入异种移植物和早期通过人类肿瘤异种移植的既定细胞系也表明 AZD7762是体内有效的化学和放射敏化剂，为进行临床提供了强烈的动力审判。具体目标2是使用异种移植模型来建立进行临床试验的基础将AZD7762与GEM +辐射相结合，评估药物时间表的作用。 AIM 2的结果将帮助定义我们随后的临床试验的设计。特定目标3是使用 AZD7762与局部晚期，无法切除的患者的GEM +辐射结合胰腺癌。我们将使用宝石 +辐射的组合，然后是宝石，并结合根据AIM 2中建议的时间表，剂量降低AZD7762。我们假设MTD AZD7762将与仅使用GEM的当前I期试验确定的AZD7762相似（即添加保形辐射将对AZD7762的MTD产生最小的影响，与GEM结合使用）。另外，我们假设AZD7762在MTD处施用时会抑制替代正常组织中的CHK1活性并且可能以较低的剂量。