Tailoring New Drugs in Pancreatic Cancer

描述（申请人提供）：胰腺癌是一种致命疾病。新药的经验开发并没有带来任何有意义的生存改善。迫切需要新的战略来防治这一疾病。我们已经开发并优化了一种低传代异种移植模型，该模型可能允许个体化治疗胰腺癌患者。将手术切除时获得的新鲜胰腺癌组织植入裸鼠体内。可以用抗癌药物治疗异种移植肿瘤，以确定其体内活性。在以往的研究中，我们已经掌握了这一模型，并获得了较高的接受率和良好的体内结果。我们还表明，在组织学、基因突变和选择的基因表达水平上，异种移植肿瘤与产生它们的原发肿瘤的生物学特征非常相似。在小鼠中连续传代不会影响肿瘤对我们初步测试的药物的抗性/敏感性，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，该模型也非常适合研究预测药物反应和/或耐药性的生物标志物。本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。待检验的假设是基于模型的药物选择对患者的治疗效果优于随机选择。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胰腺癌切除术患者的一组异种移植肿瘤的活性；b)进行II期临床试验，其中在小鼠体内移植肿瘤的患者将在进展时使用模型选择的新药进行治疗；3)探索肿瘤组织对治疗药物反应的生物学标志物。我们期望这种方法将验证低传代异种移植模型的使用，以预测对药物的敏感性。如果正确，该模型将对发现预测药物反应的生物标志物以及作为胰腺癌临床开发药物的筛选模型具有宝贵的价值。

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.