Analysis of Patient Tumor Responses to Apo2L/TRAIL

来自该小组的初步和已发表的数据首次显示，患者的肿瘤在一个特定的时间内生长。 SCID小鼠/异种移植物模型可以对被Apo 2L/ TRAIL杀死高度敏感， TNF家族的死亡配体，临床前有相当大的乐观。然而，我们的初步 观察还表明，一些肿瘤对Apo 2L/TRAIL具有抗性，这意味着某些患者可能 没有从Apo 2L/TRAIL疗法中获益。本研究的总体目标是获得一个清晰的 了解患者中Apo 2L/TRAIL敏感性与耐药性的自然发生程度 肿瘤，并确定敏感性与耐药性的标志物以及克服 阻力使用我们的患者肿瘤模型，我们将测试这一假设，即靶向这两个互补的 与Apo 2L/TRAIL组合同时的凋亡信号传导途径（即外源性和内源性） 化疗将加强凋亡信号，促进增强对耐药恶性肿瘤的杀伤。 细胞此外，在对Apo 2L/TRAIL显示天然敏感性的肿瘤中，该试剂可以增加 化疗的治疗效果，从而能够降低剂量和减少副作用。我们预计 该组合疗法将靶向具有不同水平的 因此，它可以对单独的单一药物敏感，从而可以靶向更广泛的肿瘤细胞群体。 该提案的综合目标将：目标1）表征一组新获得的患者 胰腺和结肠肿瘤关于它们对Apo 2UTRAILAim 2）的敏感性分析凋亡 Apo 2L/TRAIL敏感与耐药肿瘤中的信号传导途径，以鉴定能够 选择将受益于这种治疗的患者;目的3）分析和比较凋亡信号传导 在Apo 2L/TRAIL单独治疗、单独化疗或联合治疗期间， 这些药物相互作用以增强肿瘤杀伤的机制。由于大量的 由于我们已经获得了丰富的经验和初步数据，我们的团队在执行此分析方面处于独特的位置 控制对Apo 2L/TRAIL的敏感性/抗性的因素 将提供Apo 2L/TRAIL临床应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.