Evaluation of Src Inhibition in Pancreas Cancer

胰腺癌中 Src 抑制的评价

基本信息

批准号：
7692984
负责人：
Wells A. Messersmith
金额：
$ 31.43万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-29 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7692984
关键词：
Acute Aftercare Biological Biological Markers Biopsy Cancer Biology Cancer Etiology Cancer Patient Cancer Therapy Evaluation Program Cell Adhesion Cessation of life Clinic Clinical Clinical Protocols Clinical Trials Combined Modality Therapy Correlative Study Data Development Diagnosis Disease Distant Drug Combinations Drug Kinetics Erlotinib Evaluation Exhibits Fluorouracil Functional disorder Funding Future Genes Goals Grant Human Image Immunohistochemistry Incidence Invaded Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of pancreas Measures Mentors Metastatic Neoplasm to the Liver Methods Modeling Morality Neoplasm Metastasis Oral Organ Pancreatic Adenocarcinoma Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Phase II Clinical Trials Phase III Clinical Trials Phenotype Phosphotransferases Positron-Emission Tomography Pre-Clinical Model Principal Investigator Property Proteins Protocols documentation Qualifying Resistance Running Sampling Signal Pathway Signal Transduction Site Stable Disease Staging Testing Tissues Toxic effect Travel Tumor Tissue Western Blotting Writing Xenograft Model Xenograft procedure base cancer cell capecitabine clinical efficacy cytotoxic design drug efficacy epithelial to mesenchymal transition fluorodeoxyglucose positron emission tomography gemcitabine gene discovery human data improved indexing inhibitor/antagonist interest migration neoplastic cell novel pre-clinical public health relevance receptor research study response treatment effect tumor

项目摘要

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.

描述（由申请人提供）：胰腺癌是每年癌症死亡的第四大原因，2007 年估计有超过 37,000 例新病例和超过 32,000 例死亡。尽管最近对胰腺癌生物学的了解有所提高，但 5 年生存率仍为 4%尽管采用多学科治疗。尽管对胰腺癌生物学有了新的认识并采用了新疗法，但生存率仍然较低，这表明迫切需要改进治疗。为此，创建了一种源自患者的胰腺腺癌外植体异种移植模型“PancBank”，以帮助开发胰腺癌的新疗法。一种新兴靶点是非受体激酶 c-SRC。这种蛋白调节多个级联反应，影响细胞粘附、迁移和侵袭，当这些因素失调时，肿瘤细胞就会破坏其微环境，不依赖于正常的调节信号，迁移到远处并侵入宿主组织。这种表型的结果是转移，这是癌细胞导致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。我们使用 PancBank 中的新型口服 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蛋白质印迹发现了有趣的线索。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）在吉西他滨耐药的转移性胰腺癌患者中的 II 期临床和生物学研究。这是一项由 CTEP 批准并资助的协议，通过第二阶段联盟运行，该提案的首席研究员撰写了该协议并担任其国家主席。该临床试验利用肿瘤前和肿瘤后活检、PET 扫描和 PK 研究等相关研究，为验证和扩展胰腺癌人类异种移植实验的结果提供了一个非常独特的机会。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识别的一部分患者将从 AZD0530 中获益。这些研究将确定未来可在更大规模的 III 期研究中进行测试的生物标志物，并为与 Src 抑制剂的药物组合指明方向。公共健康相关性：这笔赠款的目的是探索胰腺癌的哪些特性与 Src 抑制剂的脆弱性或耐药性相关。我们将使用多种方法来分析临床方案 NCI#7602“AZD0530 在先前治疗的转移性胰腺癌中的 II 期试验”中的患者肿瘤样本。 AZD0530是一种新型口服Src抑制剂，Src是几十年前发现的第一个致癌基因，希望研究结果能够帮助指导我们在临床上更好地使用此类药物。