Predicting Response of Pancreatic Tumors to Therapy

描述（由申请人提供）：成功开发和应用胰腺癌靶向治疗的主要挑战是缺乏有助于选择新临床试验患者的预测标志物。由于这些新的、基于癌症生物学的治疗剂被设计成阻断高度特异性的途径，这些途径在任何给定患者的肿瘤中可能是或可能不是活性的或必需的，因此许多患者目前进入临床试验，在这些临床试验中，他们几乎没有机会获得益处，并且重要的是，失去了宝贵的时间来尝试可能更有益的替代方法。然而，能够确定可以更好地预测给定患者用给定疗法成功的机会的标志物仍然是非常有问题的，并且需要在治疗之前、期间和之后获得患者肿瘤材料，以便比较响应的分子基础。我们的实验室正在利用SCID小鼠中胰腺肿瘤患者来源的手术标本的生长作为评估胰腺癌新靶向治疗疗效的模型，并作为分析观察到的敏感性或耐药性基础的材料来源。我们正在进行的研究的总体目标是清楚地了解患者肿瘤对新疗法的敏感性与耐药性的程度，并确定敏感性与耐药性的标志物以及克服耐药性的策略。我们目前正在评估的一种治疗方法是Apo 2L/TRAIL，一种TNF家族的凋亡诱导死亡配体，其具有相当大的临床前（和现在的临床）乐观性。我们的数据首次表明，许多患者的胰腺肿瘤生长在SCID小鼠/异种移植模型是高度敏感的Apo 2L/ TRAIL。然而，其他患者的肿瘤是耐药的，因此我们预测某些患者可能不会从这种治疗中受益。我们目前正在开发一组患者的胰腺肿瘤，我们已经确定了对Apo 2L/TRAIL的敏感性或抗性，并比较了作为凋亡信号传导途径的关键组分或作为该信号传导抑制剂的蛋白质的表达水平。该分析目前通过蛋白质印迹分析和免疫组织化学进行。在此R 03应用程序中，我们正在申请资金，对这些同样宝贵的患者来源的样本进行首次差异基因表达分析，以便1）阐明蛋白质表达差异的基础，2）鉴定与这些肿瘤对Apo 2L的敏感性或抗性相关的新基因或基因表达模式。TRAIL可用作标记物，用于选择最有可能从这种新的和令人兴奋的靶向治疗中受益的患者。由于我们已经有了表征肿瘤的样本，这项研究可能会对胰腺癌患者选择最有可能成功的临床试验的能力产生直接的积极影响。

DESCRIPTION (provided by applicant): A major challenge for the successful development and application of targeted therapies for pancreas cancer is the absence of predictive markers which would assist in patient selection for new clinical trials. Since these novel, cancer biology-based therapeutics are designed to block highly specific pathways which may or may not be active or essential in any given patient's tumor, many patients currently enter clinical trials in which they have little chance of receiving benefit, and importantly, lose valuable time in which to try alternative approaches that could have been more beneficial. However, being able to determine markers which could better predict a given patients chances for success with a given therapy is still extremely problematic and requires access to patient tumor material before, during and after treatment in order to compare the molecular basis of response. Our laboratory is utilizing the growth of patient-derived surgical specimens of pancreatic tumors in SCID mice as a model for evaluating the efficacy of new targeted therapies for pancreatic cancer and as a source of material with which to analyze the basis of the observed sensitivity or resistance. The overall goal of our ongoing research is to obtain a clear understanding of the degree to which sensitivity vs. resistance to novel therapies occurs in patient tumors and to identify both markers for sensitivity vs. resistance as well as strategies for overcoming resistance. One therapeutic that we are currently evaluating is Apo2L/TRAIL, an apoptosis inducing death ligand of the TNF family for which there is considerable pre-clinical (and now clinical) optimism. Our data show for the first time that many patients' pancreatic tumors grown in the SCID mouse/xenograft model are highly sensitive to Apo2L/ TRAIL. However, other patients' tumors are resistant and thus we predict that certain patients may not benefit from this therapy. We are currently developing a panel of patients' pancreas tumors for which we have determined the sensitivity or resistance to Apo2L/TRAIL and are comparing the expression levels of proteins that are either critical components of apoptotic signaling pathways or implicated as inhibitors of this signaling. This analysis is currently being carried out by western blot analysis and immunohistochemistry. In this R03 application, we are requesting funding to carry out the first differential gene expression analysis of these same invaluable patient-derived samples in order to 1) clarify the basis for differences in protein expression and 2) to identify novel genes or patterns of gene expression related to sensitivity or resistance of these tumors to Apo2L/TRAIL that could be used as markers for selecting patients who have the best chance of benefiting from this new and exciting targeted therapy. Since we already have the samples of characterized tumors, this research could have an immediate positive impact on the ability of patients with pancreatic cancer to choose the clinical trial in which they have greatest chance for success.