Predicting Response of Pancreatic Tumors to Therapy

预测胰腺肿瘤对治疗的反应

• 批准号: 7405356
• 负责人: ELIZABETH A REPASKY
• 金额: $ 8.06万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405356
• 关键词: Address; Aftercare; Apoptosis; Apoptotic; Cancer Biology; Cancer cell line; Cell Line; Cessation of life; Clinical; Clinical Trials; Colon; Combined Modality Therapy; Data; Development; Diagnosis; Exhibits; Family; Funding; Gene Expression; Genes; Genus Cola; Goals; Growth; Immunohistochemistry; Individual; Laboratories; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Modeling; Molecular; Molecular Profiling; N.I.H. Research Support; Normal Cell; Operative Surgical Procedures; Pancreas; Pancreatic Adenocarcinoma; Pathway interactions; Patient Selection; Patients; Pattern; Proteins; Range; Request for Applications; Research; Resected; Resistance; SCID Mice; Sampling; Series; Signal Pathway; Signal Transduction; Source; Specimen; TNF gene; Testing; Therapeutic; Time; Tissue-Specific Gene Expression; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumor-Derived; Up-Regulation; Western Blotting; Work; Xenograft Model; Xenograft procedure; base; cancer therapy; caspase-8; design; human TNF protein; inhibitor/antagonist; killings; member; neoplastic cell; novel; novel therapeutics; optimism; pancreatic neoplasm; pre-clinical; protein expression; research study; response; success; time use; tumor; tumor xenograft

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.

描述（由申请人提供）：成功开发和应用胰腺癌靶向治疗的一个主要挑战是缺乏有助于新临床试验患者选择的预测标记。由于这些新颖的、基于癌症生物学的疗法旨在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活跃或不活跃或必需，因此许多患者目前进入临床试验，在这些试验中他们几乎没有机会受益，重要的是，失去了尝试其他可能更有益的方法的宝贵时间。然而，能够确定能够更好地预测给定患者接受给定治疗的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、期间和之后获取患者肿瘤材料，以便比较反应的分子基础。我们的实验室正在利用 SCID 小鼠中患者来源的胰腺肿瘤手术标本的生长作为评估胰腺癌新靶向疗法疗效的模型，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中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记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 Apo2L/TRAIL，它是 TNF 家族的一种诱​​导细胞凋亡的死亡配体，对其临床前（现在是临床）持相当乐观的态度。我们的数据首次显示，许多在 SCID 小鼠/异种移植模型中生长的患者胰腺肿瘤对 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疗法中受益。我们目前正在开发一组患者的胰腺肿瘤，我们已经确定了这些患者对 Apo2L/TRAIL 的敏感性或耐药性，并且正在比较作为细胞凋亡信号传导途径的关键组成部分或涉及该信号传导的抑制剂的蛋白质的表达水平。目前正在通过蛋白质印迹分析和免疫组织化学进行该分析。在此 R03 申请中，我们请求资金对这些同样宝贵的患者来源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) 识别新基因或基因模式与这些肿瘤对 Apo2L/TRAIL 的敏感性或耐药性相关的表达，可以用作选择最有机会从这种新的、令人兴奋的靶向治疗中受益的患者的标志物。由于我们已经拥有特征性肿瘤的样本，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。