The long-term goal of our research is to identify and develop novel and efficacious therapeutic regimens forthe treatment of human cancer, particularly head and neck cancer (HNC). The current application aimsspecifically at targeting death receptor-mediated apoptotic pathways for the treatment of HNC, particularlymetastatic 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 andWestern blotting data indicate that highly metastatic HNC cell lines express increased levels of deathreceptor 5 (DR5), FADD, caspase-8 and caspase-9 and low levels of c-FLIP(L) although they exhibitundetectable levels of TRAIL and high levels of c-FLIP(S). Importantly these cell lines are highly sensitive toexogenous TRAIL treatment. Perifosine, the first oral alkylphospholipid with Akt-inhibitory activity in clinicaltrials, further upregulates the expression of DR5, reduces c-FLIP levels and very effectively inducesapoptosis in these metastatic HNC cell lines. Based on these findings, we hypothesize that highly metastaticHNC cells retain high potential to undergo DR5-mediated apoptosis, albeit with dysregulated apoptoticsignaling. Thus, agents including TRAIL and perifosine that activate the DR5-mediated apoptoticpathwaymay be effective in treatment of metastatic HNC. These hypotheses will be tested by accomplishing thefollowing specific aims: 1) Determine the mechanism(s) by which perifosine and TRAIL cooperatively induceapoptosis of metastatic HNC cells; 2) Determine the efficacy of TRAIL and its combination with perifosine inan 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 betweenprimary and metastatic human HNC tissues, and evaluate their prognostic values. The accomplishmentofthese aims will allow us to assess the efficacy of TRAIL and its combination with perifosine in the treatmentof HNC, particularly metastatic HNC, in vitro and in vivo, reveal the underlying mechanisms of perifosine andTRAIL synergism, and demonstrate the role of dysregulation of the extrinsic apoptotic pathway in HNCmetastasis and its prognostic value. The results generated from this project can be directly translated toclinical practice for the better treatment of HNC patients.
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