P3 - Mechanism-Based Use of Chk1 Inhibitors in Pancreas Cancer

P3 - Chk1 抑制剂在胰腺癌中基于机制的使用

基本信息

批准号：
7893334
负责人：
THEODORE S LAWRENCE
金额：
$ 11.08万
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：
2010-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7893334
关键词：
Address Adjuvant Therapy Affect Biological Assay Biological Markers Biopsy Cancer Patient Cancer cell line Cause of Death Cell Cycle Checkpoint Cell Cycle Progression Cell Survival Chemosensitization Cisplatin Clinical Research Clinical Trials Consensus Cytotoxic agent DNA Damage DNA Repair Data Disease-Free Survival Dose Drug Delivery Systems Drug usage Exhibits Failure Future Goals Human Immunoblotting In Vitro Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Methods Modeling Molecular Motivation Normal tissue morphology Outcome Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phase III Clinical Trials Phosphorylation Proteins Radiation Radiation therapy Radiation-Sensitizing Agents Radiosensitization Randomized Relative (related person)Research Resected Resistance Role Sampling Schedule Skin Systemic Therapy Techniques Testing Therapeutic Effect Therapeutic Intervention Tissues Treatment Effectiveness Tumor Cell Line Work Xenograft Model advanced disease base chemosensitizing agent chemotherapy cytotoxic design 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 tumor

项目摘要

A strategy that shows 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 Chkl 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 Gem and radiation. Our preliminary data demonstrate that both chemo- and radiosensitization by AZD7762 vary substantially among human pancreatic tumor cell lines, and that under conditions of sensitization, AZD7762 affects several endpoints related to HRR. We also found that endpoints related to G2/M checkpoint abrogation reflected sensitization in some cases but not in others. Specific Aim 1 is to determine the mechanisms by which AZD7762 treatment affects HRR activity and sensitivity to Gem and IR in pancreatic cancer cell lines, in vitro. 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. Although the mechanistic basis for therapeutic effects of Chkl inhibitors is not yet completely understood, our data in vitro and in vivo already provide strong motivation for conducting an initial clinical trial. Specific Aim 2 is to use xenograft models to establish the basis for conducting a clinical trial combining AZD7762 with Gem and radiation. 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 and radiation in patients with resected pancreatic cancer. We will use a combination of Gem and 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 detennined 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 Chkl activity in surrogate normal tissues when administered at the MTD, and, possibly, at lower doses.

一种显示胰腺癌的巨大希望的策略是将细胞毒性治疗与消除了大多数肿瘤细胞表现出的已经繁琐的检查点功能的药物。吸毒靶标蛋白CHK1（例如AZD7762，目前正在I期临床试验中）尤其是在胰腺癌背景下的兴趣是因为CHKL还被证明在介导Rad51的活性，Rad51是同源重组修复（HRR）中的关键蛋白具有对DNA损害治疗的耐药性，并在人胰腺肿瘤中上调。长我们工作的一项目标是通过理性地改善胰腺癌患者的结果将CHK1抑制剂添加到宝石和辐射的组合中。我们的初步数据表明，AZD7762的化学和放射敏化均有很大差异在人胰腺肿瘤细胞系中，在敏化条件下，AZD7762影响与HRR有关的几个终点。我们还发现与G2/M检查点废除有关的端点在某些情况下反映了灵敏度，但在其他情况下不反映。特定目的1是确定机制 AZD7762治疗会影响胰腺癌细胞中HRR活性和对GEM和IR的敏感性线，体外。这项工作将使我们能够确定基于机制的分子终点未来的临床研究，并确定与HRR活性有关的治疗干预措施的新靶标。尽管尚未完全了解CHKL抑制剂治疗作用的机械基础，但我们的数据在体外和体内已经为进行初始临床试验提供了强大的动力。具体的目标2是使用异种移植模型来建立进行临床试验的基础 AZD7762带有宝石和辐射。 AIM 2的结果将有助于定义我们随后的设计临床试验。具体目的3是使用AZD7762与GEM和辐射一起进行临床试验切除的胰腺癌患者。我们将使用宝石和辐射的组合，然后使用基于AIM 2中建议的时间表，仅GEM，再加上剂量升级的AZD7762。假设AZD7762的MTD与使用当前I期试验中的确定的MTD相似仅宝石（即增加保形辐射将对AZD7762的MTD产生最小的影响结合宝石）。另外，我们假设AZD7762将抑制替代正常的CHKL活性组织在MTD处施用，并可能以较低的剂量给药。