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

治疗胰腺癌的一个很有希望的策略是将联合收割机细胞毒性治疗与 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试剂。的药物 靶向检查点蛋白Chk 1（如AZD 7762，目前处于I期临床试验）是特别重要的 Chkl在胰腺癌的背景下引起了人们的兴趣，因为Chkl也已被证明在胰腺癌中具有关键作用。 介导Rad 51的活性，Rad 51是同源重组修复（HRR）中的关键蛋白， 对DNA损伤治疗具有抗性，并且在人胰腺肿瘤中上调。长 我们工作的长期目标是通过合理的治疗， 将Chk 1抑制剂加入到Gem和辐射的组合中。 我们的初步数据表明，AZD 7762的化疗和放射增敏作用存在显著差异， 在人胰腺肿瘤细胞系中，在致敏条件下，AZD 7762影响 与HRR相关的几个终点。我们还发现与G2/M检查点废除相关的终点 在某些情况下反映了敏感性，但在另一些情况下则不然。具体目标1是确定机制， AZD 7762处理影响胰腺癌细胞中HRR活性和对Gem和IR的敏感性 线，在体外。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，并确定新的目标，治疗干预，有关HRR的活动。 虽然Chkl抑制剂的治疗作用的机制基础尚未完全理解， 我们的体外和体内数据已经为进行初步临床试验提供了强大的动力。具体 目的2是利用异种移植模型建立基础，进行临床试验， AZD 7762与宝石和辐射。目标2的结果将有助于确定我们随后的设计 临床试验 具体目标3是进行一项临床试验，使用AZD 7762与Gem和放射联合治疗， 胰腺癌切除患者。我们将使用宝石和辐射的组合， 根据目标2中建议的时间表，Gem单药联合剂量递增的AZD 7762。我们 假设AZD 7762的MTD与当前I期试验中确定的MTD相似， 单独使用Gem（即添加适形辐射对AZD 7762的MTD影响最小， 与Gem结合）。此外，我们假设AZD 7762将抑制替代正常人中的Chkl活性， 当以MTD和可能的较低剂量给药时，

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.