TNF Blockade in Pancreatic Cancer Patients

描述（由申请人提供）：晚期胰腺腺癌患者预后不良，中位生存期不足12个月，明显需要更有效的治疗。此外，胰腺癌患者常因恶病质、厌食、恶心/呕吐和腹痛而虚弱。促炎细胞因子如肿瘤坏死因子(TNF) α、白细胞介素6 （IL-6）和白细胞介素1 （IL-1）在胰腺癌患者中均被发现升高，除了可能直接促进肿瘤进展外，还与引起许多这些症状有关。抗癌治疗的一个潜在目标是阻断肿瘤坏死因子的作用。我们假设TNF阻断应该使化疗更耐受，应该改善生活质量，应该延缓肿瘤进展的时间。在目前的建议中，我们寻求在转移性或复发性胰腺癌患者的试点试验中联合标准化疗（吉西他滨）和TNF阻断与可溶性TNF受体分子（依那西普）。我们将评估TNF阻断是否可以改善化疗获得的临床获益反应、生活质量和6个月癌症无进展生存率。此外，将从外周血单核细胞裂解物中获得一系列水平的TNF和其他炎性细胞因子，以及TNF刺激肿瘤生长的候选途径转录因子NF-kappaB。在接受吉西他滨单药治疗的10名患者的对照组中，还将测量生活质量、细胞因子和NF-kappaB水平。观察到TNF阻断患者的生活质量或无进展生存的益处，将鼓励在适当的随机临床试验中对这种新策略进行评估。

DESCRIPTION (provided by applicant): The poor prognosis of patients with advanced pancreatic adenocarcinoma, with a median survival of less than 12 months, indicates an obvious need for more effective treatments. In addition, patients with pancreatic carcinoma are frequently debilitated by cachexia, anorexia, nausea/vomiting and abdominal pain. Pro-inflammatory cytokines like tumor necrosis factor (TNF) alpha, interleukin 6 (IL-6) and interleukin 1 (IL-1) have all been found to be elevated in pancreatic cancer patients and have been implicated in causing many of these symptoms, in addition to the possibility of directly promoting tumor progression. One potential target for anticancer therapy is blocking the effects of TNF. We hypothesize that TNF blockade should make chemotherapy more tolerable, should improve quality of life and should retard the time to tumor progression. In the current proposal, we seek to combine standard chemotherapy (gemcitabine) and TNF blockade with soluble TNF receptor molecules (etanercept) in a pilot trial in patients with metastatic or recurrent pancreatic cancer. We will evaluate if TNF blockade can improve the clinical benefit response, quality of life and the rate of cancer progression-free survival at six months obtained with chemotherapy. In addition, serial levels of TNF and other inflammatory cytokines, as well as the transcription factor NF-kappaB, a candidate pathway through which TNF stimulates tumor growth, will be obtained from peripheral blood mononuclear cells lysates. Quality of life and levels of the cytokines and NF-kappaB will also be measured in a control group of 10 patients receiving gemcitabine as a single agent. The observation of benefits in either quality of life or progression-free survival in patients undergoing TNF blockade would encourage evaluation of this novel strategy in properly powered randomized clinical trials.