TARGETING DEATH RECEPTOR-MEDIATED APOPTOSIS FOR HEAD AND NECK CANCER

我们研究的长期目标是确定和开发新的和有效的治疗方案 人类癌症的治疗，特别是头颈部癌症(HNC)。当前应用程序的目标是 特别是针对死亡受体介导的凋亡通路治疗HNC 肿瘤坏死因子相关的凋亡诱导配体在转移性HNC中的作用 (TRAIL)或环磷腺苷联合TRAIL治疗转移性鼻咽癌我们的基因阵列和 Western blotting数据表明，高转移的HNC细胞株表达的死亡水平增加 受体5(DR5)、FADD、Caspase-8和Caspase-9以及低水平的c-flip(L)，尽管它们表现出 无法检测到的TRAIL水平和高水平的c-Flip(S)。重要的是，这些细胞系对 外源性TRAIL治疗。Perifosine是临床上第一个具有Akt抑制活性的口服烷基磷脂 试验，进一步上调DR5的表达，降低c-flip水平，并非常有效地诱导 这些转移性HNC细胞系中的细胞凋亡。基于这些发现，我们假设高度转移性 HNC细胞仍有很高的潜力接受DR5介导的凋亡，尽管存在凋亡调节失调 发信号。因此，包括TRAIL和Perifosine在内的激活DR5介导的细胞凋亡途径的药物 可能是治疗转移性HNC的有效方法。这些假设将通过实现 具体目标如下：1)确定Perifosine和TRAIL协同诱导的机制(S 转移性HNC细胞的凋亡；2)检测TRAIL及其联合应用对HNC细胞的影响 HNC转移的体内模型；以及3)确定所选基因的差异表达模式 (例如，TRAIL、DR5、c-flip和caspase-8)主要参与 原发和转移的人类HNC组织，并评估其预后价值。完成…… 这些目标将使我们能够评估TRAIL的疗效以及它与派罗福辛的联合治疗。 HNC，特别是转移性HNC的体外和体内研究揭示了Perifosine和 TRAIL协同作用，并证明外源性细胞凋亡途径失调在HNC中的作用 转移及其预后价值。此项目生成的结果可以直接转换为 为更好地治疗HNC患者进行临床实践。

The long-term goal of our research is to identify and develop novel and efficacious therapeutic regimens for the treatment of human cancer, particularly head and neck cancer (HNC). The current application aims specifically at targeting death receptor-mediated apoptotic pathways for the treatment of HNC, particularly metastatic HNC, through evaluating the potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or perifosine and TRAIL in combination in the treatment of metastatic HNC. Our gene array and Western blotting data indicate that highly metastatic HNC cell lines express increased levels of death receptor 5 (DR5), FADD, caspase-8 and caspase-9 and low levels of c-FLIP(L) although they exhibit undetectable levels of TRAIL and high levels of c-FLIP(S). Importantly these cell lines are highly sensitive to exogenous TRAIL treatment. Perifosine, the first oral alkylphospholipid with Akt-inhibitory activity in clinical trials, further upregulates the expression of DR5, reduces c-FLIP levels and very effectively induces apoptosis in these metastatic HNC cell lines. Based on these findings, we hypothesize that highly metastatic HNC cells retain high potential to undergo DR5-mediated apoptosis, albeit with dysregulated apoptotic signaling. Thus, agents including TRAIL and perifosine that activate the DR5-mediated apoptoticpathway may be effective in treatment of metastatic HNC. These hypotheses will be tested by accomplishing the following specific aims: 1) Determine the mechanism(s) by which perifosine and TRAIL cooperatively induce apoptosis of metastatic HNC cells; 2) Determine the efficacy of TRAIL and its combination with perifosine in an in vivo model of HNC metastasis; and 3) Determine differential expression patterns of selected genes (e.g., TRAIL, DR5, c-FLIP, and caspase-8) primarily involved in the extrinsic apoptotic pathway between primary and metastatic human HNC tissues, and evaluate their prognostic values. The accomplishmentof these aims will allow us to assess the efficacy of TRAIL and its combination with perifosine in the treatment of HNC, particularly metastatic HNC, in vitro and in vivo, reveal the underlying mechanisms of perifosine and TRAIL synergism, and demonstrate the role of dysregulation of the extrinsic apoptotic pathway in HNC metastasis and its prognostic value. The results generated from this project can be directly translated to clinical practice for the better treatment of HNC patients.