Analysis of Patient Tumor Responses to Apo2L/TRAIL

来自该组织的初步和公布的数据首次表明，患者的肿瘤生长在 SCID小鼠/异种移植模型对新近发现的Apo2L/TRAIL致死高度敏感 肿瘤坏死因子家族的死亡配体，临床前有相当大的乐观。然而，我们的初步调查 观察还显示，一些肿瘤对Apo2L/TRAIL具有耐药性，这意味着某些患者可能 不受益于Apo2L/TRAIL疗法。拟议研究的总体目标是获得一个明确的 了解患者对载脂蛋白2L/TRAIL的自然敏感性与耐药性的关系 并确定敏感性与耐药性的标记物以及克服策略 抵抗。使用我们的患者肿瘤模型，我们将检验以两者为靶点、互补的假设 Apo2L/TRAIL同时参与的细胞凋亡信号通路(即外源性和内源性) 化疗将增强细胞凋亡信号，促进对耐药肿瘤的杀灭 细胞。此外，在对载脂蛋白2L/TRAIL表现出天然敏感性的肿瘤中，该试剂可能会增加 化疗的治疗效果，从而使更低的剂量和减少副作用。我们预计 这种联合疗法将针对不同水平的恶性细胞 仅对单一药物敏感，因此可能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 胰腺和结肠肿瘤对Apo2UTRAIL的敏感性目的2)分析细胞凋亡 Apo2L/TRAIL敏感与耐药肿瘤中的信号通路以识别将使 选择将从这种治疗中受益的患者；目标3)分析和比较细胞凋亡信号 载脂蛋白2L/TRAIL单独治疗、单独化疗或联合治疗期间的通路 这些药物相互作用以增强肿瘤杀伤力的机制。因为有大量的 根据我们获得的经验和初步数据，我们的团队处于进行这一分析的独特地位 控制Apo2L/TRAIL敏感性/耐药性的因素 将提供Apo2L/TRAIL临床使用方面的实用相关知识。

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.