We have demonstrated that TGF-alpha/EGFR upregulation in SCCHN is due to activated gene transcription and that downmodulation of either TGF- alpha or EGFR results in decreased proliferation of SCCHN but not normal cells. Preliminary data suggest that TGF-alpha/EGFR signaling in SCCHN involves activation of Stat1alpha/beta, Stat3alpha/beta, and Stat5a/b and that downmodulation of either Stat3 or Stat5b using antisense oligonucleotides results in inhibition of SCCHN proliferation. The importance of this autocrine pathway is underscored by our finding that protein expression levels of TGF-alpha or EGFR in the primary SCCHN are significant and independent predictors of decreased survival. Therefore, we propose to test the hypothesis that the loss of growth control in SCCHN is mediated through acquisition of a TGF-alpha/EGFR autocrine signaling pathway, with the ultimate aim of designing novel preventive and therapeutic regimens which target this pathway.
In specific aim 1 we propose to characterize the effects of modulating TGF- alpha and/or EGFR expression on cell growth and STAT activation in normal and transformed mucosal squamous epithelial cells by: a) determining the consequences of TGF-alpha or EGFR downmodulation in vitro; b) examining the anti-tumor response and the effect of TGF-alpha and/or EGFR downmodulation in vivo; c) determining the effect of elevated levels of TGF-alpha or EGFR; and d) characterizing the impact of TGF-alpha or EGFR modulation on STAT protein activation/expression.
In specific aim 2 we propose to determine the relative contribution of State3alpha and beta isoforms and Stat5b to the growth stimulatory effects of TGF-alpha/EGFR autocrine signaling in SCCHN by: a) examining the relative activation/expression levels of Stat3alpha, Stat3beta or Stat5b in SCCHN and normal cells in vitro and in vivo; b) determining the proliferative effect of Stat3alpha, Stat3beta, or Stat5b overexpression in SCCHN cells in vitro; and c) elucidating the consequences of downmodulation of Stat3alpha, Stat3beta or Stat5b on SCCHN cells in vitro and in vivo.
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