Prostate Cancer: Transition to Androgen-Independence

描述(申请人提供)：雄激素剥夺仍然是晚期前列腺癌(CAP)患者的标准治疗方法，并导致大多数男性的疾病缓解。然而，CAP最终复发，此后患者的中位生存期不到1年。因此，从雄激素刺激到经常性生长的转变是CAP进展的关键时刻。该计划项目的统一假设是，在雄激素剥夺治疗期间，低水平雄激素、丝裂原信号和辅助激活剂激活雄激素受体(AR)，介导CAP的复发生长。在本P01的前三年，我们证明了AR在大多数复发性CAP中呈野生型，AR蛋白在良性前列腺和复发性CAP中的表达水平相似，复发性CAP中的AR是超敏的(由雌雄激素和有丝分裂原反式激活)，复发性CAP中的睾酮和DHT的组织水平足以激活AR，前列腺内的干细胞具有神经内分泌特征，CAP异种移植的新生血管起源于人而不是小鼠，并出现雄激素反应。此次更新由3个密切相关的项目组成。项目1将测试这一假设，即在雄激素剥夺治疗期间，通过对组织雄激素和/或雄激素受体的攻击可以防止或推迟CAP的复发。使用CAP细胞系、CAP异种移植和临床标本，将阐明复发CAP细胞中雄激素水平的组织水平产生的机制。通过抑制雄激素的形成和加速其降解，可以防止雄激素在复发的帽子组织中积聚。雄激素受体将使用AR显性阴性和使用慢病毒载体系统传递的siRNA来灭活。项目2将检验这一假设，即在低雄激素水平存在的情况下，AR的重新激活是由有丝分裂原信号驱动的。EGF和Hereglin增强复发性CAP中AR转录活性的机制将被确定，重点是AR磷酸化、p160共激活因子和下游信号转导。将定义参与EGF、hereglin和AR辅活化子和辅阻遏子调节的AR结构域，并阐明AR拮抗剂失去抑制的机制。可能在AR反式激活中发挥作用的新型辅助调节因子将被测试其作为治疗靶点的潜力。项目3将测试CAP复发起源于前列腺内原始的、多潜能干细胞样细胞的假设。基础细胞、血管内皮细胞和神经内分泌细胞在能够在相对缺乏雄激素的情况下生长的帽细胞群体的出现中的作用将在短期人良性前列腺和CAP异种移植、TRAMP和CWR22模型以及在雄激素剥夺治疗之前和期间获得的一系列前列腺活检中进行研究。

DESCRIPTION (provided by applicant): Androgen deprivation remains the standard therapy for patients with advanced prostate cancer (CAP) and causes disease remission in most men. However, CaP eventually recurs and thereafter the median survival of patients is less than 1 year. Thus, the transition from androgen-stimulated to recurrent growth represents a critical juncture in the progression of CaP. The Program Project's unifying hypothesis is that activation of the androgen receptor (AR) by low level androgens, mitogen signaling and coactivators mediates recurrent growth of CaP during androgen deprivation therapy. In the first three years of this P01, we demonstrated that AR is wild-type in most recurrent CaP, AR protein is expressed at similar levels in benign prostate and recurrent CaP, AR in recurrent CaP is hypersensitive (transactivated by femtomolar DHT and mitogens), tissue levels of testosterone and DHT within recurrent CaP appear sufficient for AR activation, stem-like cells within the prostate have neuroendocrine characteristics and the neovasculature of CaP xenografts is human not mouse in origin and appear androgen-responsive. The renewal consists of 3 closely-related projects. Project 1 will test the hypothesis that recurrence of CaP during androgen deprivation therapy can be prevented or delayed by attack upon tissue androgens and/or the androgen receptor. The mechanism of generation of tissue levels of androgens in recurrent CaP cells will be elucidated using CaP cell lines, CaP xenografts and clinical specimens. The accumulation of androgens in recurrent CaP tissue will be prevented by inhibiting their formation and augmenting their degradation. The androgen receptor will be inactivated using AR-dominant negatives and siRNA delivered using the lentiviral vector system. Project 2 will test the hypothesis that AR reactivation in the presence of low androgen levels is driven by mitogen signaling. Mechanisms by which EGF and heregulin enhance AR transcriptional activity in recurrent CaP will be determined with a particular emphasis upon AR phosphorylation, p160 coactivators and downstream signaling. The AR domains involved in EGF, heregulin and AR coactivator and corepressor regulation will be defined and the mechanism for loss of inhibition by AR antagonists elucidated. Novel coregulators that may have a role in AR transactivation will be tested for their potential as therapeutic targets. Project 3 will test the hypothesis that CaP recurrence originates from primitive, pluri-potential stem-like cells within the prostate. The role of the basal cell, vascular endothelium and neuroendocrine cells in the emergence of a population of CaP cells capable of growth in relative androgen absence will be examined in short-term human xenografts of benign prostate and CaP, the TRAMP and CWR22 models, and serial prostate biopsies obtained prior to and during androgen deprivation therapy.