Individualized Treatment of Pancreatic Cancer

胰腺癌的个体化治疗

基本信息

批准号：
7242609
负责人：
MANUEL HIDALGO
金额：
$ 28.26万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-06 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7242609
关键词：
Address Animals Antineoplastic Agents Area Biological Biological Markers Biopsy Cell Line Clinical Drug Development Clinical Research Clinical Trials Network Conduct Clinical Trials Data Development Diagnosis Disease Disease Progression Drug Delivery Systems Drug resistance Enrollment Excision Fine needle aspiration biopsy Gene Expression Gene Mutation General Population Goals Histology Hospitals Implant Individual Institution Malignant neoplasm of lung Malignant neoplasm of pancreas Medical Methods Modeling Molecular Mus Nude Mice Numbers Operative Surgical Procedures Outcome Patient Selection Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Population Positioning Attribute Pre-Clinical Model Predisposition Primary Neoplasm Principal Investigator Property Protocols documentation Publishing Rate Recurrence Research Research Ethics Committees Research Personnel Resected Resistance Resources Screening procedure Series Simulate Specimen Staging Standards of Weights and Measures System Testing Therapeutic Intervention Time Tissues Translating Tumor Tissue Work Xenograft Model Xenograft procedure antitumor agent base cancer cell cancer therapy clinical efficacy design follow-up gemcitabine improved in vivo innovation malignant breast neoplasm mouse model multidisciplinary novel novel therapeutics pancreatic neoplasm pre-clinical programs response success therapeutic target tumor tumor growth tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is a lethal disease. Empirical development of new drugs has not resulted in any meaningful improvement in survival. New strategies are urgently needed to combat this disease. We have developed and optimized a low-passage xenograft model that may permit an individualize approach to the treatment of patients with pancreatic cancer. Freshly pancreatic cancer tissues obtained at the time of surgical resection of pancreatic cancer are implanted in nude mice. Xenografted tumors can be treated with anticancer agent to determine their in vivo activity. In previous studies we have mastered this model and have a high take on rate and excellent in vivo results. We have also shown that the xenografted tumors closely resemble at the histology, gene mutation and selected gene expression data the biological features of the primary tumor from which they were generated. Sucessive passage in mice does not influence the resistant/susceptibility properties of the tumors to the drugs we have preliminarily tested and does not result in mayor changes in biological features. Because tumors can be indefinitely propagated in the mice the model is also very well suited to investigate biological markers that predict response and/or resistance to drugs. This translational application is to utilize the above mentioned preclinical model for cancer treatment. The hypothesis to be tested is that model-based selection of drugs for patient's treatment will result in better outcome than expected with conventional drugs. We propose the following three Specific Aims: 1) to determine the activity of a series of available anticancer agents against a set of xenografted tumors obtained from patients with resected pancreatic cancer; 2) to conduct a phase II clinical trial in which patients whose tumor was xenografted in the mice will be treated at the time of progression with model-selected agent and; 3) to explore biological markers of response to treatment agents in tumor tissues. We expect this approach will validate the use of the low-passage xenograft model to predict susceptibility to a drug. If correct, this model will then be invaluable to discover biomarkers predicting drug response and as a screening model to select drug for clinical development in pancreatic cancer.

描述（由申请人提供）：胰腺癌是一种致命疾病。新药的实证开发并未对生存率产生任何有意义的改善。迫切需要新的策略来对抗这种疾病。我们开发并优化了低传代异种移植模型，该模型可能允许对胰腺癌患者进行个体化治疗。将手术切除胰腺癌时获得的新鲜胰腺癌组织植入裸鼠体内。异种移植肿瘤可以用抗癌剂治疗以确定其体内活性。在之前的研究中，我们已经掌握了这个模型，并且具有很高的接受率和出色的体内结果。我们还表明，异种移植肿瘤在组织学、基因突变和选定的基因表达数据方面与产生它们的原发肿瘤的生物学特征非常相似。在小鼠体内的连续传代不会影响肿瘤对我们初步测试的药物的耐药/敏感性特性，也不会导致生物学特征的重大变化。由于肿瘤可以在小鼠体内无限繁殖，因此该模型也非常适合研究预测药物反应和/或耐药性的生物标记。该转化应用是利用上述临床前模型进行癌症治疗。要测试的假设是，基于模型选择用于患者治疗的药物将比传统药物带来更好的结果。我们提出以下三个具体目标：1）确定一系列可用的抗癌药物对从胰腺癌切除患者体内获得的一组异种移植肿瘤的活性； 2) 进行 II 期临床试验，其中肿瘤异种移植到小鼠体内的患者将在疾病进展时接受模型选择的药物治疗； 3）探索肿瘤组织中治疗药物反应的生物标志物。我们期望这种方法将验证使用低传代异种移植模型来预测对药物的敏感性。如果正确，该模型对于发现预测药物反应的生物标志物以及作为选择胰腺癌临床开发药物的筛选模型将具有无价的价值。