Analysis of Patient Tumor Responses to Apo2L/TRAIL

患者肿瘤对 Apo2L/TRAIL 的反应分析

• 批准号: 7034793
• 负责人: ELIZABETH A REPASKY
• 金额: $ 30.33万
• 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 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7034793
• 关键词: CD95 molecule; SCID mouse; antineoplastics; apoptosis; biomarker; combination cancer therapy; drug resistance; drug screening /evaluation; human tissue; immune tolerance /unresponsiveness; pancreas neoplasms; patient oriented research; tumor necrosis factor alpha; xenotransplantation

DESCRIPTION (provided by applicant): 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/TRAIL therapy. 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 Apo2L/TRAIL; 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/TRAIL alone, 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.

描述（由申请人提供）：该小组的初步和公开数据首次表明，在 SCID 小鼠/异种移植模型中生长的患者肿瘤对 Apo2L/TRAIL 的杀死高度敏感，Apo2L/TRAIL 是最近鉴定的死亡配体TNF家族对此在临床前抱有相当大的乐观态度。然而，我们的初步观察也表明，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 治疗中受益。拟议研究的总体目标是清楚地了解 Apo2L/TRAIL 敏感性与耐药性在患者肿瘤中自然发生的程度，并确定敏感性与耐药性的标记物以及克服耐药性的策略。使用我们的患者肿瘤模型，我们将测试以下假设：同时使用 Apo2L/TRAIL 与化疗结合靶向两种互补的细胞凋亡信号通路（即外在和内在）将增强细胞凋亡信号并促进增强对耐药恶性细胞的杀伤。此外，在对 Apo2L/TRAIL 表现出天然敏感性的肿瘤中，该试剂可以提高化疗的治疗效果，从而降低剂量并减少副作用。我们预计联合疗法将针对对单一药物具有不同敏感性水平的异质恶性细胞群，从而可能针对更广泛的肿瘤细胞群。 该提案的综合目标将是： 目标 1) 表征一组新获得的胰腺和结肠肿瘤患者对 Apo2L/TRAIL 的敏感性；目标 2) 分析 Apo2L/TRAIL 敏感与耐药肿瘤中的细胞凋亡信号通路，以确定标记物，从而能够选择将从该治疗中受益的患者；目标 3) 分析和比较单独使用 Apo2L/TRAIL、单独化疗或联合治疗期间的细胞凋亡信号通路，以确定这些药物相互作用以增强肿瘤杀伤的机制。由于我们获得了大量的经验和初步数据，我们的团队处于独特的地位，可以对患者肿瘤进行这种分析，以了解控制 Apo2L/TRAIL 敏感性/耐药性的因素。此外，这些信息将为以下方面提供实用的相关知识： Apo2L/TRAIL 的临床应用。