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; 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）：该组的初步和发布的数据首次表明，在SCID小鼠/异种移植模型中生长的患者肿瘤可能对被APO2L/ TRAIL杀死，这是TNF家族的最近确定的死亡配体，这有相当大的前临床前的乐观。但是，我们的初步观察结果还表明，某些肿瘤对APO2L/TRAIL具有抗性，这表明某些患者可能不会受益于APO2L/TRAIL治疗。拟议的研究的总体目标是清楚地了解患者肿瘤中APO2L/TRAIL敏感性与耐药性自然发生的程度，并确定两个标记敏感性与耐药性以及克服抗药性的策略。使用我们的患者肿瘤模型，我们将测试以下假设：靶向两种互补的凋亡信号通路（即外在和内在的）与APO2L/TRAIL同时使用APO2L/TRAIL与化学疗法结合使用，可以增强凋亡信号，并促进增强抗药性恶性细胞的增强。此外，在对APO2L/TRAIL表现出自然敏感性的肿瘤中，该试剂可以增加化学疗法的治疗作用，从而降低剂量和副作用降低。我们预计，联合疗法将针对单独对单个药物敏感性差异的恶性细胞的异质群体，从而靶向更广泛的肿瘤细胞。 该提案的综合目的将：目标1）表征一组新鲜获得的患者胰腺和结肠肿瘤，以其对APO2L/TRAIL的敏感性；目标2）分析Apo2L/TRAIL敏感性与耐药性肿瘤中的凋亡信号通路，以识别能够选择将从这种治疗中受益的患者；目标3）单独使用APO2L/TRAIL治疗期间分析和比较凋亡信号通路，单独化疗或联合疗法，以识别这些药物相互作用以增强肿瘤杀死的机制。由于我们获得了大量的经验和初步数据，因此我们的小组处于独特的位置，可以对患者肿瘤进行分析，以控制对APO2L/TRAIL的敏感性/抵抗力的因素，此信息将在APO2L/TRAR的临床使用方面提供实用的，相关的知识。