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）：来自该组的初步和已发表的数据首次显示，在SCID小鼠/异种移植物模型中生长的患者肿瘤对被Apo 2L/ TRAIL杀死高度敏感，Apo 2L/ TRAIL是最近鉴定的TNF家族的死亡配体，其具有相当大的临床前乐观性。然而，我们的初步观察也表明，一些肿瘤对Apo 2L/TRAIL具有耐药性，这意味着某些患者可能无法从Apo 2L/TRAIL治疗中获益。拟议研究的总体目标是清楚地了解患者肿瘤中Apo 2L/TRAIL敏感性与耐药性的自然发生程度，并确定敏感性与耐药性的标志物以及克服耐药性的策略。使用我们的患者肿瘤模型，我们将测试以下假设：用Apo 2L/TRAIL与化疗组合同时靶向两种互补的凋亡信号传导途径（即外源性和内源性）将加强凋亡信号并促进抗性恶性细胞的增强杀伤。此外，在对Apo 2L/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，从而能够降低剂量并减少副作用。我们预期联合治疗将靶向对单一药物具有不同敏感性水平的异质性恶性细胞群体，从而可能靶向更广泛的肿瘤细胞群体。 本提案的综合目标是：目标1）表征一组新获得的胰腺和结肠肿瘤患者对Apo 2L/TRAIL的敏感性;目标2）分析Apo 2L/TRAIL敏感性与抗性肿瘤中的凋亡信号传导途径，以鉴定能够选择将受益于该治疗的患者的标志物;目的3）分析和比较Apo 2L/TRAIL单独治疗、单独化疗或联合治疗过程中的凋亡信号通路，以确定这些药物相互作用以增强肿瘤杀伤的机制。由于我们已经获得了大量的经验和初步数据，我们的团队处于独特的位置，可以对患者肿瘤进行这种分析，以确定控制Apo 2L/TRAIL敏感性/耐药性的因素。此外，这些信息将提供Apo 2L/TRAIL临床使用方面的实用相关知识。