Analysis of Patient Tumor Responses to Apo2L/TRAIL

患者肿瘤对 Apo2L/TRAIL 的反应分析

• 批准号: 7538322
• 负责人: ELIZABETH A REPASKY
• 金额: $ 30.58万
• 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 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7538322
• 关键词: Adverse effects; Apoptosis; Apoptotic; Biological; Cancer cell line; Cell Line; Cessation of life; Clinical; Colonic Neoplasms; Combined Modality Therapy; Data; Development; Dose; Family; Goals; In Situ; Knowledge; Ligands; Manuscripts; Mediating; Mitochondria; Modeling; Non-Malignant; Operative Surgical Procedures; Pancreas; Pathway interactions; Patient Selection; Patients; Population; Population Heterogeneity; Positioning Attribute; Property; Publishing; Reagent; Research; Resistance; SCID Mice; Sampling; Signal Pathway; Signal Transduction; Specimen; TNF gene; TNFSF10 gene; Testing; Therapeutic; Therapeutic Effect; Time; Treatment Efficacy; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumor-Derived; Work; Xenograft Model; Xenograft procedure; base; cancer cell; cancer therapy; cell killing; chemotherapy; clinically relevant; experience; killings; neoplastic cell; optimism; pre-clinical; receptor; research study; response; time use; tumor

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.

该组的初步和已发布的数据首次表明，患者肿瘤在A中生长 SCID鼠标/异种移植模型可能对被Apo2L/ Trail杀死的高度敏感，这是最近确定的 TNF家族的死亡配体具有相当大的临床前乐观。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，这意味着某些患者可以 不受APO2L/Traftherapy的好处。拟议研究的总体目标是获得清晰的 了解APO2L/TRAIL敏感性与抗药性自然发生的程度 肿瘤并确定两个标记的灵敏度与抵抗力以及克服的策略 反抗。使用我们的患者肿瘤模型，我们将检验以下假设，即针对两者的互补 凋亡信号通路（即外在和固有的）与Apo2L/Trail的组合同时 通过化学疗法将增强凋亡信号并促进抗性恶性肿瘤的杀戮 细胞。此外，在对APO2L/TRAIL表现出自然敏感性的肿瘤中，该试剂可能会增加 化学疗法的治疗作用，从而降低剂量和副作用降低。我们期望 这种组合疗法将针对具有差异水平的恶性细胞的异质种群 仅对单个药物的敏感性，因此可能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 胰腺肿瘤和结肠肿瘤对Apo2utrail Aim的敏感性2）分析凋亡 apo2l/trail敏感与耐药性肿瘤中的信号通路，以识别将启用的标记 选择将从这种治疗中受益的患者；目标3）分析和比较凋亡信号传导 用Apo2L/Trailalonon，单独化疗或联合疗法治疗期间的途径以鉴定 这些药物相互作用以增强肿瘤杀伤的机制。由于大量 我们获得的经验和初步数据，我们的小组处于独特的位置来执行此分析 患者肿瘤的因素控制了对Apo2L/Trail的敏感性/抗性，此信息 将在APO2L/TRAIL的临床使用方面提供实用的相关知识。