Targeted Therapy of Prostate Cancer

前列腺癌的靶向治疗

基本信息

批准号：
6602790
负责人：
YOUNG E WHANG
金额：
$ 14.55万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2005-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): 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 is 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 is to characterize the effect of GW2016 in combination with anti-androgens and chemotherapeutic agents in vivo. The third aim is 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.

描述（由申请人提供）：尽管晚期前列腺癌被雄激素消融治疗，但大多数患者都会发展为激素难治阶段，这总是致命的。通过自分泌信号循环的生长因子信号通路的组成型激活是前列腺癌中雄激素独立性发展的一种潜在机制。最近对受体酪氨酸激酶（包括表皮生长因子受体（EGFR）家族成员）的特异性和有效抑制剂的最新可用性促进了这些酪氨酸激酶在前列腺癌发展和发展中的作用的表征。 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.此外，GW2016比EGFR选择性抑制剂更有效地抑制前列腺癌细胞的生长，并抑制雄激素诱导的基因表达。 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代理商。我们将集中精力遵循特定目标。第一个目的是表征GW2016（EGFR/HER-2抑制剂）对免疫缺陷小鼠中CWR22前列腺癌异种移植物体内生长速率的影响。第二个目的是表征GW2016在体内结合抗雄激素和化学治疗剂的作用。第三个目的是研究前列腺癌异种移植物和原发性肿瘤中的EGFR/HER-2酪氨酸激酶自分泌轴。该项目的成功完成将验证以下概念：抑制EGFR家族激酶信号通路是一种合理的策略，可以迅速转化为前列腺癌患者的临床试验。