Mechanism-Based Use of Chk1 Inhibitors in Pancreas Cancer

项目摘要 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药物治疗相结合 这消除了大多数肿瘤细胞已经表现出的脆弱的检查点功能。药物靶向 检查点蛋白Chk 1（如AZD 7762，目前处于I期临床试验）在免疫学中特别受关注。 因为Chk 1也被证明在介导胰腺癌的活性中具有关键作用， Rad 51是同源重组修复（HRR）中的一种关键蛋白，与DNA抗性有关。 损伤性治疗，并且在人胰腺肿瘤中上调。我们工作的长期目标是 合理添加Chk 1抑制剂改善胰腺癌患者的预后 吉西他滨（Gem）+放射的组合。我们的初步数据显示，AZD 7762是一种有效的化疗药物， 和人胰腺肿瘤细胞系的放射增敏剂，其既降低HRR又消除G2/M 检查站具体目标1是确定细胞周期检查点消除和细胞周期调控的相对作用。 AZD 7762在化疗和放射增敏中的HRR抑制。这项工作将使我们能够识别 基于机制的分子终点将在未来的临床研究中询问，并确定新的靶点 用于与HRR活性相关的治疗干预。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。我们的初步结果使用这两个 作为异种移植物和早期传代人肿瘤异种移植物植入的已建立的细胞系也显示， AZD 7762是一种有效的体内化疗和放射增敏剂，为开展临床研究提供了强大的动力。 审判具体目标2是使用异种移植模型建立进行临床试验的基础 AZD 7762联合Gem +放疗，评价药物给药方案的作用。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是进行临床试验， AZD 7762联合Gem +放疗治疗局部晚期不可切除的 胰腺癌我们将使用Gem +辐射的组合，然后单独使用Gem，结合 AZD 7762剂量递增，基于目标2中建议的时间表。我们假设， AZD 7762将与目前I期试验中单独使用Gem的结果相似（即， 适形放射对AZD 7762与Gem联合给药的MTD影响最小）。另外我们 假设AZD 7762以MTD给药时会抑制替代正常组织中的Chk 1活性， 而且可能是低剂量

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.