Although advanced prostate cancer is treated with androgen ablation, most patients progress to the hormone refractory stage, which is invariably fatal. Constitutive activation of growth factor signaling pathways, through an autocrine signaling loop, is one potential mechanism of the progression to androgen independence in prostate cancer. Recent availability of specific and potent inhibitors of receptor tyrosine kinases, including members of epidermal growth factor receptor (EGFR) family members, facilitates characterization of the role of these tyrosine kinases in the development and progression of prostate cancer. Using the novel inhibitor (GW2016) capable of inhibiting both EGFR and HER-2/neu/c-ErbB-2 tyrosine kinases, we show that there may be an autocrine activation of HER-2 and HER-3 in prostate cancer cells and that GW2016, the dual inhibitor of EGFR and HER-2, inhibits growth of prostate cancer cells in vitro and induces apoptosis or G1 cell cycle arrest. Furthermore, GW2016 inhibits growth of prostate cancer cells more potently than EGFR-selective inhibitors and suppresses androgen-induced gene expression. Therefore, we propose to test the hypothesis that autocrine activation of the EGFR tyrosine kinase family members, including EGFR and HER-2/neu, is required for the continued viability and growth of prostate cancer tumors in vivo, and that inhibition of EGFR family tyrosine kinases will lead to inhibition of growth of prostate cancer in vivo and sensitization to apoptotic stimuli, such as chemotherapeutic agents. We will concentrate on following specific aims.
The first aim i s to characterize the effect of GW2016, the EGFR/HER-2 inhibitor, on the in vivo growth rate of CWR22 prostate cancer xenografts in immunodeficient mice.
The second aim i s to characterize the effect of GW2016 in combination with anti-androgens and chemotherapeutic agents in vivo.
The third aim i s to investigate the EGFR/HER-2 tyrosine kinase autocrine signaling axes in prostate cancer xenografts and in primary tumors. Successful completion of this project will validate the concept that inhibition of the EGFR family kinase signaling pathway is a rational strategy that can be rapidly translated into clinical trials in prostate cancer patients.
