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细胞毒治疗与 消除大多数肿瘤细胞已经表现出的脆弱的检查点功能的药物。毒品，即 靶向检查点蛋白Chk1(如目前处于I期临床试验的AZD7762)具有特殊意义 对胰腺癌的兴趣，因为Chk1也被证明在 介导RAD51的活性，RAD51是同源重组修复中的关键蛋白 对DNA损伤治疗具有抵抗力，在人类胰腺肿瘤中上调。《长河》 我们工作的长期目标是通过合理的治疗来改善胰腺癌患者的预后 在宝石和辐射的组合中加入Chk1抑制剂。 我们的初步数据表明，AZD7762的化疗和放射增敏作用有很大差异 在人胰腺肿瘤细胞系和致敏条件下，AZD7762作用于 与HRR相关的几个端点。我们还发现，与G2/M检查点取消相关的端点 在某些情况下反映了敏感化，但在其他情况下没有。具体目标1是通过以下方式确定机制 AZD7762对胰腺癌细胞HRR活性及对Gem和IR敏感性的影响 体外培养的细胞系。这项工作将使我们能够识别要询问的基于机制的分子端点 未来的临床研究，并确定与HRR活动相关的治疗干预的新靶点。 虽然Chk1抑制剂的治疗作用的机制基础还不完全清楚， 我们在体外和体内的数据已经为进行初步临床试验提供了强大的动力。特定的 目的2是使用异种移植模型为进行临床试验奠定基础。 AZD7762，宝石和辐射。目标2的结果将有助于定义我们后续的 临床试验。 具体目标3是使用AZD7762联合宝石和放射治疗进行临床试验 手术切除的胰腺癌患者。我们将使用宝石和辐射的组合，然后 GEM单独，结合剂量递增的AZD7762，根据AIM 2中建议的时间表。我们 假设AZD7762的MTD将类似于在当前的I期试验中使用 GEM单独(即增加共形辐射对AZD7762的MTD影响最小) 与宝石相结合)。此外，我们还假设AZD7762将抑制替代正常的Chk1活性 在MTD给药时，可能会以较低的剂量给药。

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.