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， 治疗人类癌症，特别是头颈癌（HNC）。当前应用程序旨在 特别是针对死亡受体介导的细胞凋亡途径来治疗HNC，特别是 转移性HNC，通过评估肿瘤坏死因子相关凋亡诱导配体的潜力 在一个实施方案中，本发明提供了一种用于治疗转移性HNC的药物组合物，该药物组合物包括TRAIL或哌立福辛和TRAIL的组合。我们的基因阵列 蛋白质印迹数据表明，高转移性HNC细胞系表达增加的死亡水平， 受体5（DR 5）、FADD、半胱天冬酶-8和半胱天冬酶-9以及低水平的c-FLIP（L），尽管它们表现出 检测不到水平的TRAIL和高水平的c-FLIP（S）。重要的是，这些细胞系对 外源性TRAIL治疗。哌立福新，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DR 5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，我们假设高转移性肿瘤 HNC细胞保持经历DR 5介导的细胞凋亡的高潜力，尽管存在失调的细胞凋亡。 信号因此，包括TRAIL和哌立福辛的激活DR 5介导的抗肿瘤途径的试剂 可有效治疗转移性HNC。这些假设将通过完成 1）确定哌立福新和TRAIL协同诱导肿瘤细胞凋亡的机制， 2）确定TRAIL及其与哌立福新的组合在转移性HNC细胞凋亡中的功效; HNC转移的体内模型;和3）确定所选基因的差异表达模式 (e.g., TRAIL、DR 5、c-FLIP和半胱天冬酶-8）主要参与细胞凋亡的外源性途径。 原发性和转移性人HNC组织，并评估其预后价值。关于我们 这些目标将使我们能够评估TRAIL及其与哌立福新联合治疗的疗效， 的HNC，特别是转移性HNC，在体外和体内，揭示了哌立福新的潜在机制， TRAIL协同作用，并证明HNC中外源性凋亡途径失调的作用。 转移及其预后价值。该项目产生的结果可以直接转化为 为更好地治疗HNC患者提供临床实践。

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.