Mechanism-Based Use of Chk1 Inhibitors in Pancreas Cancer

描述(申请人提供)：一种治疗胰腺癌的策略显示出巨大的希望，就是将细胞毒性治疗与药物相结合，以消除大多数肿瘤细胞已经表现出的微弱的检查点功能。针对检查点蛋白Chk1的药物(如目前处于I期临床试验的AZD7762)在胰腺癌的背景下特别感兴趣，因为Chk1也被证明在调节RAD51的活性方面发挥关键作用，RAD51是同源重组修复(HRR)中的关键蛋白，与对DNA损伤治疗的抵抗有关，并且在人类胰腺肿瘤中上调。我们工作的长期目标是通过在吉西他滨(Gem)+放疗的组合中合理添加Chk1抑制剂来改善胰腺癌患者的预后。我们的初步数据显示，AZD7762是一种有效的人胰腺癌细胞株的化疗和放射增敏剂，它既降低了HRR，又取消了G2/M检查点。具体目的1是确定细胞周期检查点取消和HRR抑制在AZD7762的化疗和放射增敏中的相对作用。这项工作将使我们能够在未来的临床研究中确定要询问的基于机制的分子终点，并确定与HRR活动相关的治疗干预的新靶点。我们假设，取消检查点和抑制HRR在(TO GEM)和AZD7762中各自发挥着关键但不同的作用。我们使用已建立的细胞系作为异种移植和早期传代人肿瘤异种移植的初步结果也表明，AZD7762在体内是一种有效的化学和放射增敏剂，为进行临床试验提供了强大的动力。具体目标2是使用异种移植模型，为进行AZD7762与Gem+放射联合的临床试验奠定基础，评估药物方案的作用。AIM 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是使用AZD7762联合Gem+放射治疗局部晚期、无法切除的胰腺癌患者进行临床试验。根据AIM 2中建议的时间表，我们将结合使用Gem+辐射和单独使用Gem，并结合剂量递增的AZD7762。我们假设AZD7762的MTD将类似于目前单独使用Gem的I期试验中确定的MTD(即，添加适形辐射将对AZD7762与Gem联合使用的MTD影响最小)。此外，我们假设AZD7762在MTD给药时，以及可能在较低剂量下，将抑制代理正常组织中Chk1的活性。 公共卫生相关性：该项目直接旨在改善胰腺癌患者的治疗，通过确定人类胰腺肿瘤之间的生物学差异，确定当一种新型药物(“检查点抑制剂”)添加到这种疾病的当前标准治疗(吉西他滨加放射)中时，患者的反应如何。该研究计划既包括对被诊断为无法切除(无法手术)的胰腺癌患者的临床试验，也包括使用来自胰腺癌患者的经过充分研究的细胞系的实验室研究。

DESCRIPTION (provided by applicant): 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 upregulate 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. PUBLIC HEALTH RELEVANCE: This project is directly aimed at improving treatment of patients with pancreatic cancer, by identifying the biological differences among human pancreatic tumors that determine how well patients respond when a new type of drug ("checkpoint inhibitor") is added to the current standard treatment for this disease (Gemcitabine plus radiation). The research plan includes both a clinical trial for patients diagnosed with unresectable (inoperable) pancreatic cancer, and laboratory studies using well-studied cell lines derived from pancreatic cancer patients.