Evaluation of Src Inhibition in Pancreas Cancer

胰腺癌中 Src 抑制的评价

• 批准号: 7529896
• 负责人: WELLS A Messersmith
• 金额: $ 29.6万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-29 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7529896
• 关键词: Acute; Appendix; Biological; Biological Markers; Biopsy; Cancer Biology; Cancer Etiology; Cancer Patient; Cancer Therapy Evaluation Program; Cell Adhesion; Cessation of life; Class; 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; Numbers; Oral; Organ; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Personal Satisfaction; 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; Proliferative Index; Property; Proteins; Protocols documentation; Public Health; Purpose; Qualifying; Rate; Resistance; Running; Sampling; Signal Pathway; Signal Transduction; Site; Stable Disease; Staging; Testing; Tissues; Toxic effect; Travel; Tumor Tissue; Week; Western Blotting; Writing; Xenograft Model; Xenograft procedure; base; cancer cell; capecitabine; clinical efficacy; cytotoxic; day; design; drug efficacy; epithelial to mesenchymal transition; fluorodeoxyglucose positron emission tomography; gemcitabine; human data; improved; indexing; inhibitor/antagonist; interest; migration; neoplastic cell; novel; pre-clinical; receptor; research study; response; treatment effect; tumor

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）：胰腺腺癌是每年癌症死亡的第四个主要原因，有超过37,000例新病例和2007年估计的32,000多例死亡。尽管最近对胰腺癌生物学的了解提高了，但尽管有多种模态治疗，但5年生存率仍为4％。尽管对胰腺癌生物学有了新的了解，但生存率持续较差，而新型疗法的纳入表明，急需改善治疗。为此，已经创建了一种患者来源的胰腺腺癌异种移植模型“ pancbank”，以帮助开发胰腺癌的新疗法。一个新兴靶标是非受体激酶C-SRC。该蛋白质调节了影响细胞粘附，迁移和侵袭的多个级联反应，这些因素在失调时会导致肿瘤细胞破坏其微环境，前往远处的部位并入侵与正常调节信号无关的宿主组织。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。与大多数靶向疗法一样，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。我们已经使用了新型的口服SRC抑制剂来比较敏感和耐药的人胰腺癌外植体，并使用基因分析分析和Western印迹发现了有趣的铅。下一步是在诊所探索这些初步发现。目的是在耐吉西他滨转移性胰腺癌患者中完成AZD0530（一种口服SRC抑制剂）AZD0530的II期临床和生物学研究。这是通过II阶段联盟运行的CTEP批准和资助的协议，该提案的首席研究员撰写了该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，这项临床试验是一个高度独特的机会，可以限定和扩展胰腺癌中人异种移植实验的结果。由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患者子集将从AZD0530获得好处。这些研究将鉴定出可以将来在更大的III期研究中测试的生物标志物，并指向与SRC抑制剂进行药物组合的道路。公共卫生相关性：这笔赠款的目的是探索胰腺癌的特性与SRC抑制剂有关的脆弱性或抵抗性有关。我们将使用几种方法来分析临床方案NCI＃7602的患者肿瘤样品，“ AZD0530在先前治疗的转移性胰腺癌中的II期试验”。 AZD530是一种新型的SRC口服抑制剂，它是几十年前发现的第一个引起癌症的基因，希望这些结果将有助于我们在诊所更好地使用此类药物。