Targeted Therapy of Prostate Cancer

前列腺癌的靶向治疗

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6602790
• 关键词: androgens; apoptosis; athymic mouse; autocrine; biological signal transduction; cell proliferation; epidermal growth factor; gene expression; growth factor receptors; kinase inhibitor; male castration; messenger RNA; neoplasm /cancer chemotherapy; neoplastic growth; paclitaxel; phosphorylation; prostate neoplasms; protein tyrosine kinase; protooncogene; xenotransplantation

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）：虽然晚期前列腺癌可以通过雄激素消融治疗，但大多数患者会进展到激素难治期，这总是致命的。通过自分泌信号环路的生长因子信号通路的组成性激活是前列腺癌进展为雄激素独立性的一种潜在机制。最近出现的受体酪氨酸激酶（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，有助于表征这些酪氨酸激酶在前列腺癌发生和进展中的作用。使用能够抑制 EGFR 和 HER-2/neu/c-ErbB-2 酪氨酸激酶的新型抑制剂 (GW2016)，我们发现前列腺癌细胞中可能存在 HER-2 和 HER-3 的自分泌激活，并且GW2016是EGFR和HER-2的双重抑制剂，在体外抑制前列腺癌细胞的生长并诱导细胞凋亡或G1细胞周期停滞。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。因此，我们建议检验以下假设：EGFR 酪氨酸激酶家族成员（包括 EGFR 和 HER-2/neu）的自分泌激活是前列腺癌肿瘤体内持续生存和生长所必需的，并且抑制 EGFR 家族酪氨酸激酶将导致体内前列腺癌生长的抑制以及对细胞凋亡刺激（例如化疗剂）的敏感性。我们将集中精力实现具体目标。第一个目标是表征 EGFR/HER-2 抑制剂 GW2016 对免疫缺陷小鼠 CWR22 前列腺癌异种移植物体内生长速率的影响。第二个目标是表征 GW2016 与抗雄激素和化疗药物联合使用的体内效果。第三个目标是研究前列腺癌异种移植物和原发性肿瘤中的 EGFR/HER-2 酪氨酸激酶自分泌信号轴。该项目的成功完成将验证抑制 EGFR 家族激酶信号通路是一种合理策略的概念，可以快速转化为前列腺癌患者的临床试验。