Analysis of Patient Tumor Responses to Apo2L/TRAIL

患者肿瘤对 Apo2L/TRAIL 的反应分析

• 批准号: 7346989
• 负责人: ELIZABETH A REPASKY
• 金额: $ 30.19万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-10 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7346989
• 关键词: Adverse effects; Apoptosis; Apoptotic; Biological; Cancer cell line; Cell Line; Cessation of life; Clinical; Colonic Neoplasms; Combined Modality Therapy; Data; Development; Dose; Family; Goals; In Situ; Knowledge; Ligands; Manuscripts; Mediating; Mitochondria; Modeling; Non-Malignant; Operative Surgical Procedures; Pancreas; Pathway interactions; Patient Selection; Patients; Population; Population Heterogeneity; Positioning Attribute; Property; Publishing; Range; Reagent; Research; Resistance; SCID Mice; Sampling; Signal Pathway; Signal Transduction; Specimen; TNF gene; TNFSF10 gene; Testing; Therapeutic; Therapeutic Effect; Time; Treatment Efficacy; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumor-Derived; Work; World Health Organization; Xenograft Model; Xenograft procedure; base; cancer cell; cancer therapy; cell killing; chemotherapy; clinically relevant; experience; human TNF protein; killings; neoplastic cell; optimism; pre-clinical; receptor; research study; response; time use; tumor

Preliminary and published data from this group show for the first time that patients' tumors grown in a SCID mouse/xenograft model can be highly sensitive to being killed by Apo2L/ TRAIL, a recently identified death ligand of the TNF family for which there is considerable pre-clinical optimism. However, our preliminary observations also show that some tumors are resistant to Apo2L/TRAIL,implying that certain patients may not benefit from Apo2L/TRAILtherapy. The overall goal of the proposed research is to obtain a clear understanding of the degree to which Apo2L/TRAIL sensitivity vs. resistance naturally occurs in patient tumors and to identify both markers for sensitivity vs. resistance as well as strategies for overcoming resistance. Using our patient tumor model, we will test the hypothesis that targeting the two, complementary apoptotic signaling pathways (i.e. extrinsic and intrinsic) simultaneously with Apo2L/TRAIL in combination with chemotherapy will strengthen the apoptotic signal and facilitate enhanced killing of resistant malignant cells. Furthermore, in tumors displaying a natural sensitivity to Apo2L/TRAIL,this reagent could increase the therapeutic effects of chemotherapy, thereby enabling lower doses and reduced side effects. We expect that combination therapy will target a heterogeneous population of malignant cells with differential levels of sensitivity to single agents alone and may thereby target a broader population of tumor cells. The integrated aims of this proposal will: Aim 1) characterize a panel of freshly obtained patient pancreatic and colon tumors with regard to their sensitivity to Apo2UTRAIL Aim 2) analyze apoptotic signaling pathways in Apo2L/TRAIL sensitive vs. resistant tumors to identify markers that will enable selection of patients who will benefit by this treatment; Aim 3) analyze and compare apoptotic signaling pathways during treatment with Apo2L/TRAILalone, chemotherapy alone or combination therapy to identify mechanisms by which these agents interact to enhance tumor killing. Because of the extensive amount of experience and preliminary data we have acquired, our group is in a unique position to perform this analysis of patient tumors for factors that control sensitivity/resistance to Apo2L/TRAIL Moreover, this information will provide practical, relevant knowledge in terms of the clinical use of Apo2L/TRAIL.

该小组的初步和已发表的数据首次表明，患者的肿瘤在 SCID 小鼠/异种移植模型对 Apo2L/TRAIL 的杀死高度敏感，Apo2L/TRAIL 是最近发现的一种 TNF 家族的死亡配体，临床前对此抱有相当大的乐观态度。然而，我们的初步 观察结果还表明，一些肿瘤对 Apo2L/TRAIL 具有耐药性，这意味着某些患者可能 无法从 Apo2L/TRAIL 疗法中获益。拟议研究的总体目标是获得明确的 了解患者体内 Apo2L/TRAIL 敏感性与耐药性自然发生的程度 肿瘤并确定敏感性与耐药性的标记物以及克服策略 反抗。使用我们的患者肿瘤模型，我们将测试针对两个互补的假设 与 Apo2L/TRAIL 组合同时进行细胞凋亡信号通路（即外在和内在） 与化疗结合将增强细胞凋亡信号并促进增强杀灭耐药恶性细胞 细胞。此外，在对 Apo2L/TRAIL 表现出天然敏感性的肿瘤中，该试剂可以增加 化疗的治疗效果，从而可以降低剂量并减少副作用。我们期望 联合疗法将针对具有不同水平的异质恶性细胞群 对单一药物的敏感性，因此可以针对更广泛的肿瘤细胞群。 该提案的综合目标将： 目标 1) 描述一组新获得的患者的特征 胰腺和结肠肿瘤对 Apo2UTRAIL 的敏感性目标 2) 分析细胞凋亡 Apo2L/TRAIL 敏感与耐药肿瘤中的信号通路，以确定能够实现的标记物 选择将从该治疗中受益的患者；目标 3) 分析和比较细胞凋亡信号传导 使用 Apo2L/TRAIL 单独治疗、单独化疗或联合治疗期间的通路来确定 这些药物相互作用以增强肿瘤杀伤的机制。由于数量广泛 我们获得的经验和初步数据，我们的团队处于执行此分析的独特位置 患者肿瘤控制 Apo2L/TRAIL 敏感性/耐药性的因素此外，此信息 将提供 Apo2L/TRAIL 临床使用方面的实用相关知识。