Evaluation of Src Inhibition in Pancreas Cancer

描述（由申请人提供）：胰腺腺癌是每年癌症死亡的第四大原因，2007年估计有37,000多例新病例和32,000多例死亡。尽管最近对胰腺癌生物学的了解有所提高，但尽管采用了多种治疗方法，5年生存率仍为4%。尽管对胰腺癌生物学有了新的认识，并结合了新的治疗方法，但生存率仍然很低，这表明迫切需要改进治疗方法。为此，一种患者源性胰腺腺癌移植异种移植模型“PancBank”已经被创建，以帮助开发胰腺癌的新疗法。一个新出现的靶点是非受体激酶c-SRC。该蛋白调节影响细胞粘附、迁移和侵袭的多个级联反应，当这些因素失调时，肿瘤细胞可以破坏其微环境，移动到远处并入侵宿主组织，而不依赖于正常的调节信号。这种表型的结果是转移，这是癌细胞引起器官功能障碍并最终死亡的关键机制。与大多数靶向治疗一样，寻找药物疗效的相关生物标志物以正确选择患者至关重要。我们已经在PancBank中使用了新型口服Src抑制剂来比较敏感和耐药的人类胰腺癌外植体，并通过基因谱分析和Western blotting发现了有趣的线索。下一步是在临床中探索这些初步发现。目标是完成AZD0530（一种口服Src抑制剂）在吉西他滨耐药转移性胰腺癌患者中的II期临床和生物学研究。这是一个ctep批准和资助的协议，通过第二阶段财团运行，该提案的主要研究者撰写了协议并担任其国家主席。使用相关研究，包括肿瘤前和肿瘤后活检，PET扫描和PK研究，该临床试验代表了一个高度独特的机会，以确定和扩展胰腺癌人类异种移植实验的结果。我们的初步数据支持的中心假设是，可以通过我们的相关研究以预测方式确定的一部分患者将受益于AZD0530。这些研究将确定可在未来更大规模的III期研究中进行测试的生物标志物，并为与Src抑制剂联合用药指明方向。公共卫生相关性：本拨款的目的是探索胰腺癌的哪些特性与Src抑制剂的易感性或耐药性相关。我们将使用几种方法分析临床方案NCI#7602中的患者肿瘤样本，“AZD0530在先前治疗的转移性胰腺癌中的II期试验”。AZD0530是一种新型的口服Src抑制剂，是几十年前发现的首批致癌基因之一，希望这一结果能够指导我们在临床中更好地使用这类药物。

DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma is the fourth leading cause of cancer deaths annually, with over 37,000 new cases and over 32,000 deaths estimated for 2007. Despite recent improved understanding of pancreas cancer biology, the 5-year survival remains at 4% despite multimodality therapy. The continued poor survival despite the new understanding of pancreatic cancer biology and the incorporation of novel therapies demonstrates an acute need for improvement in therapy. To this end, a patient-derived pancreatic adenocarcinoma explant xenograft model, the "PancBank", has been created to help develop novel therapies for pancreatic cancer. One emerging target is the non-receptor kinase, c-SRC. This protein regulates multiple cascades that impact cellular adhesion, migration and invasion, factors that when dysregulated enable tumor cells to disrupt their microenvironment, travel to distant sites and invade host tissues independent of normal regulatory signals. The result of this phenotype is metastasis, the critical mechanism by which cancer cells cause organ dysfunction and ultimately death. As with most targeted therapies, it is critically important to search for correlative biomarkers of drug efficacy in order to properly select patients. We have used novel oral Src inhibitors in the PancBank to compare sensitive and resistant human pancreas cancer explants, and have found interesting leads using gene profiling analysis and Western blotting. The next step is to explore these preliminary findings in the clinic. The goal is to complete a phase II clinical and biological study of AZD0530, an oral Src inhibitor, in gemcitabine-resistant metastatic pancreas cancer patients. This is a CTEP-approved and funded protocol run through the Phase II Consortium, and the principal investigator of this proposal wrote the protocol and serves as its national chair. Using correlative studies including pre- and post-tumor biopsies, PET scans, and PK studies, this clinical trial represents a highly unique opportunity to qualify and extend the results of the human xenograft experiments in pancreas cancer. The central hypothesis, which is supported by our preliminary data, is that a subset of patients who can be identified in predictive manner with our correlative studies will derive benefit from AZD0530. These studies will identify biomarkers that can be tested in a larger phase III study in the future, and also point the way towards drug combinations with Src inhibitors. PUBLIC HEALTH RELEVANCE: The purpose of this grant is to explore what properties of pancreas cancer are associated with vulnerability, or resistance, to Src inhibitors. We will use several methods to analyze patient tumor samples from the clinical protocol NCI#7602, "A Phase II Trial of AZD0530 in Previously Treated Metastatic Pancreas Cancer." AZD0530 is a novel oral inhibitor of Src, which was of the first cancer-causing genes discovered several decades ago, and it is hoped the results will help guide us to better use of such drugs in the clinic.