Tailoring New Drugs in Pancreatic Cancer

定制治疗胰腺癌的新药

基本信息

批准号：
8043927
负责人：
MANUEL HIDALGO
金额：
$ 20.52万
依托单位：
SPANISH NATIONAL CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-21 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8043927
关键词：
Address Adverse effects Aftercare Antineoplastic Agents Arts Biological Biological Markers Biological Markers Clinic Clinical Clinical Drug Development Clinical Research Clinical Trials Collaborations Collection Data Development Diagnosis Disease Disease Progression Drug resistance Enrollment Erlotinib Excision Failure Gene Expression Gene Mutation Genomics Goals Hand Histology Hospitals Implant Individual Informed Consent Institutes Institution Knowledge Life Malignant Neoplasms Malignant neoplasm of pancreas Measurable Medical Methods Modeling Molecular Monoclonal Antibodies Mus New Agents Nude Mice Operative Surgical Procedures Outcome Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Positioning Attribute Postoperative Period Pre-Clinical Model Predisposition Primary Neoplasm Property Protocols documentation Random Allocation Research Research Ethics Committees Research Personnel Resected Resistance Resources Screening procedure Series Simulate Solid Neoplasm Staging System Testing Therapeutic Time Tissues Tumor Tissue Work Xenograft Model Xenograft procedure advanced disease animal data antitumor agent base cancer cell capecitabine chemotherapy clinical efficacy combat gemcitabine hospice environment improved in vivo innovation mouse model multidisciplinary novel operation pancreatic neoplasm phase 2 study pre-clinical programs prospective response small molecule success treatment strategy tumor 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 individualized approach to the treatment of patients with pancreatic cancer. Fresh pancreatic cancer tissues obtained at the time of surgical resection 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 obtained 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 levels the biological features of the primary tumor from which they were generated. Sucessive passage in mice does not influence the resistance/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 to individualize the development of new drugs for patients with pancreatic cancer. The hypothesis to be tested is that model-based selection of drugs for patient's treatment will result in better outcome than expected with random selection. We propose the following three Specific Aims: 1) to determine the activity of a series of novel anticancer agents against a set of xenografted tumors obtained from patients with resected pancreatic cancer; b) 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 new agents 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，并获得了较高的接受率和优异的体内结果。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水平上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。此次转化应用就是利用上述临床前模型为胰腺癌患者个体化开发新药。要测试的假设是，基于模型选择用于患者治疗的药物将比随机选择的预期产生更好的结果。我们提出以下三个具体目标：1）确定一系列新型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； b) 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新药物治疗； 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。