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预测性标记物，这将有助于患者选择新的临床试验。由于这些新颖的基于癌症生物学的治疗方法被设计为阻断高度特异性的途径，这些途径在任何特定患者的肿瘤中可能是活跃的，也可能不是必需的，许多患者目前进入临床试验，他们几乎没有机会获得好处，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，能够确定能够更好地预测特定患者治疗成功机会的标记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，以便比较反应的分子基础。我们的实验室正在利用SCID小鼠胰腺肿瘤手术标本的生长，作为评估胰腺癌新靶向治疗效果的模型，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和耐药程度，并确定敏感性和耐药的标记以及克服耐药的策略。我们目前正在评估的一种治疗方法是Apo2L/TRAIL，这是TNF家族的一种诱导凋亡的死亡配体，临床前（现在临床）对其相当乐观。我们的数据首次显示，在SCID小鼠/异种移植模型中生长的许多患者的胰腺肿瘤对Apo2L/ TRAIL高度敏感。然而，其他患者的肿瘤具有耐药性，因此我们预测某些患者可能无法从这种治疗中获益。我们目前正在开发一组患者胰腺肿瘤，我们已经确定了Apo2L/TRAIL的敏感性或耐药性，并正在比较凋亡信号通路的关键成分或作为该信号通路抑制剂的蛋白质的表达水平。该分析目前正在通过免疫印迹分析和免疫组织化学进行。在这个R03应用程序中,我们要求资金开展的第一个差异基因表达分析这些无价的patient-derived样品为了1)阐明蛋白质表达差异的基础,2)来识别小说相关的基因或基因表达模式的敏感性或抵抗这些肿瘤Apo2L /小道,可以用作选择标记病人最有可能受益于这个新的和令人兴奋的靶向治疗。由于我们已经有了特征肿瘤的样本，这项研究可能会对胰腺癌患者选择他们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.