Tailoring New Drugs in Pancreatic Cancer

定制治疗胰腺癌的新药

• 批准号: 7912947
• 负责人: MANUEL HIDALGO
• 金额: $ 12.18万
• 依托单位: SPANISH NATIONAL CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912947
• 关键词: Address; Adverse effects; Aftercare; Antineoplastic Agents; 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; Histology; Hospitals; Implant; Individual; Informed Consent; Institutes; Institution; Institutional Review Boards; 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 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

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。新药的经验发展并未导致生存的任何有意义的改善。迫切需要采取新策略来打击这种疾病。我们已经开发并优化了一个低通的异种移植模型，该模型可能允许一种个性化的方法来治疗胰腺癌患者。在手术切除时获得的新鲜胰腺癌组织植入了裸鼠。异种移植肿瘤可以用抗癌剂治疗，以确定其体内活性。在先前的研究中，我们已经掌握了该模型，并获得了很高的率和优异的体内结果。我们还表明，异种移植的肿瘤在组织学，基因突变和选择基因表达上与产生的原发性肿瘤的生物学特征相似。小鼠中的成功通过不会影响肿瘤对我们先前测试的药物的抗性/敏感性，并且不会导致市长的生物学特征变化。由于肿瘤可以在小鼠中无限期地传播，因此模型也非常适合研究预测对药物反应和/或抗性的生物学标记。这种翻译应用是利用上述临床前模型来个性化胰腺癌患者新药的开发。要检验的假设是，基于模型的患者治疗药物选择将导致比随机选择预期的更好的结果。我们提出以下三个特定目的：1）确定一系列新型抗癌药的活性，以对从切除的胰腺癌患者获得的一组异种移植肿瘤； b）进行II期临床试验，在该试验中，将在模型选择的新药物进展时治疗小鼠肿瘤的患者。 3）探索肿瘤组织中对治疗剂反应的生物学标志物。我们预计这种方法将验证使用低通量异种移植模型来预测对药物的敏感性。如果正确，那么该模型将是无价的，可以发现预测药物反应的生物标志物，并作为选择胰腺癌临床发育的药物的筛查模型。