Evaluation of Src Inhibition in Pancreas Cancer

胰腺癌中 Src 抑制的评价

• 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
• 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

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例新发病例和超过32，000例死亡。尽管最近对胰腺癌生物学的理解有所提高，但尽管采用了多模态治疗，5年生存率仍为4%。尽管对胰腺癌生物学有了新的认识，并采用了新的治疗方法，但生存率仍然很低，这表明迫切需要改进治疗方法。为此，已经创建了患者来源的胰腺癌外植体异种移植物模型“PancBank”，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。这种蛋白质调节影响细胞粘附、迁移和侵袭的多个级联反应，这些因素在失调时使肿瘤细胞能够破坏其微环境，不依赖于正常的调节信号而移动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。我们在PancBank中使用了新型口服Src抑制剂来比较敏感和耐药的人胰腺癌外植体，并使用基因分析和蛋白质印迹法发现了有趣的线索。下一步是在临床上探索这些初步发现。该研究的目的是完成一项关于口服Src抑制剂AZD 0530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，通过第二阶段联盟运行，该提案的主要研究者编写了该协议，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，这项临床试验代表了一个非常独特的机会，以资格和扩大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患者子集将从AZD 0530中获益。这些研究将确定可以在未来更大的III期研究中测试的生物标志物，并为Src抑制剂的药物组合指明方向。公共卫生关系：这项资助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。我们将使用几种方法分析临床方案NCI#7602“AZD 0530治疗既往接受过治疗的转移性胰腺癌的II期试验”中的患者肿瘤样本。“AZD 0530是一种新型的Src口服抑制剂，Src是几十年前发现的第一个致癌基因，希望结果将有助于指导我们在临床上更好地使用此类药物。