Analysis of Patient Tumor Responses to Apo2L/TRAIL

描述(申请人提供)：这个小组的初步和已发表的数据首次表明，在SCID小鼠/异种移植模型中生长的患者的肿瘤可以对被Apo2L/TRAIL杀死高度敏感，Apo2L/TRAIL是最近发现的一种肿瘤坏死因子家族的死亡配体，临床前对此相当乐观。然而，我们的初步观察也显示，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。这项拟议研究的总体目标是明确了解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志物以及克服耐药性的策略。利用我们的患者肿瘤模型，我们将检验这样一种假设，即同时针对这两个互补的凋亡信号通路(即外在和内在)与Apo2L/TRAIL结合化疗将增强凋亡信号，并促进对耐药恶性肿瘤细胞的增强杀伤。此外，在对Apo2L/TRAIL表现出天然敏感性的肿瘤中，这种试剂可以提高化疗的疗效，从而使更低的剂量和减少副作用成为可能。我们预计，联合治疗将针对对单一药物具有不同程度敏感性的不同恶性细胞群体，从而可能针对更广泛的肿瘤细胞群体。 这项建议的综合目标将：目的1)分析一组新获得的患者胰腺和结肠癌患者对Apo2L/TRAIL的敏感性；目的2)分析Apo2L/TRAIL敏感和耐药肿瘤中的细胞凋亡信号通路，以确定能够选择将从这种治疗中受益的患者的标志物；目的3)分析和比较Apo2L/TRAIL单独治疗、单用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控制Apo2L/TRAIL敏感性/耐药性的因素分析。此外，这些信息将为Apo2L/TRAIL的临床应用提供实用的相关知识。

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.