Delineate the Role of GSTP1 in Advanced Prostate Cancer

项目摘要/摘要 前列腺癌是美国男性癌症相关死亡的第二大原因。第一 晚期转移性前列腺癌的治疗方法是激素疗法。虽然最初 不幸的是，这种疾病通常在其积极的激素治疗中复发- 耐药的形式，这是前列腺癌特异性死亡率的主要原因。因此，迫切需要 确定驱动侵袭性疾病的机制，并开发新的策略来克服晚期 难治性前列腺癌。 我们最近发现GSTP1蛋白在耐药前列腺癌中显著上调。 我们有强有力的初步证据表明，GSTP1可能在驱动攻击性的过程中发挥作用 前列腺癌，可能是这种晚期疾病的一个有前途的治疗靶点。我们最近做了 研究表明，GSTP1在激素治疗抵抗的前列腺癌中显著升高， 抑制GSTP1可抑制前列腺癌的生长。 拟议项目的主要目标是： 1)检测GSTP1在晚期前列腺癌中的功能作用。 2)检测GSTP1抑制剂单独及与顺铂联合治疗侵袭性白血病的可能性 使用NEPC患者来源的异种移植(PDX)模型的临床前环境中的前列腺癌。 3)阐明GSTP1在晚期前列腺癌中的作用机制。 这项拟议研究的成功完成将导致：1)确定GSTP1在积极治疗中的作用- 耐药前列腺癌和2)关于新的治疗干预措施的直接新战略，以对抗 致命的疾病形式。

PROJECT SUMMARY/ABSTRACT Prostate cancer is the second leading cause of cancer associated deaths in men in the United States. The first line of treatment for men with advanced metastatic prostate cancer is hormone therapy. Although initial responses are observed, unfortunately, the disease commonly recurs in its aggressive hormone therapy- resistant form, which is largely responsible for prostate cancer-specific mortality. Thus, there is an urgent need to define the mechanisms that drive the aggressive disease and develop novel strategies to overcome advanced treatment-resistant prostate cancer. We have recently shown that GSTP1 protein is significantly upregulated in treatment-resistant prostate cancer. We have strong preliminary evidence suggesting that GSTP1 may play functional role in driving aggressive prostate cancer and may represent a promising therapeutic target for the advanced disease. We have recently demonstrated that GSTP1 is significantly elevated in hormone therapy-resistant prostate cancer and that inhibition of GSTP1 suppresses prostate cancer growth. The main goals of the proposed project are: 1) test the functional role of GSTP1 in advanced prostate cancer. 2) test the therapeutic potential of GSTP1 inhibition alone and in combination with cisplatin in aggressive prostate cancer in pre-clinical settings utilizing patient-derived xenograft (PDX) models of NEPC. 3) Delineate the mechanism of action of GSTP1 in advanced prostate cancer. Successful completion of the proposed research will lead to: 1) defining the role of GSTP1 in aggressive therapy- resistant prostate cancer and 2) direct new strategies regarding novel therapeutic interventions to combat the deadly form of the disease.