Prostate Cancer: Transition to Androgen-Independence

描述（由申请人提供）：雄激素剥夺仍然是晚期前列腺癌（CAP）患者的标准治疗，并导致大多数男性疾病缓解。 然而，CaP最终复发，此后患者的中位生存期不到1年。 因此，从雄激素刺激到复发性生长的转变代表了CaP进展的关键时刻。 该项目的统一假设是，低水平雄激素、促分裂原信号传导和辅激活因子激活雄激素受体（AR）介导了雄激素剥夺治疗期间CaP的复发性生长。 在P01的前三年，我们证明AR在大多数复发性CaP中是野生型，AR蛋白在良性前列腺和复发性CaP中表达水平相似，复发性CaP中AR是高敏感的。（由飞摩尔数的DHT和有丝分裂原反式激活），复发性CaP内的睾酮和DHT的组织水平似乎足以激活AR，前列腺内的干细胞样细胞具有神经内分泌特征，CaP异种移植物的新血管系统来源于人而不是小鼠，并且表现出雄激素反应性。 该项目由3个密切相关的项目组成。 项目1将检验雄激素剥夺治疗期间CaP复发可以通过攻击组织雄激素和/或雄激素受体来预防或延迟的假设。 将使用CaP细胞系、CaP异种移植物和临床标本阐明复发性CaP细胞中产生组织水平雄激素的机制。 雄激素在复发性CaP组织中的积累将通过抑制它们的形成和增加它们的降解来防止。 将使用AR显性阴性和使用慢病毒载体系统递送的siRNA来灭活雄激素受体。 项目2将检验在低雄激素水平存在下AR再激活由促分裂原信号驱动的假设。 EGF和heregulin增强AR在复发性CaP中的转录活性的机制将被确定，特别强调AR磷酸化，p160共激活因子和下游信号转导。 参与EGF、heregulin和AR辅激活子和辅抑制子调节的AR结构域将被定义，并阐明AR拮抗剂抑制作用丧失的机制。 可能在AR反式激活中发挥作用的新型辅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多能干细胞样细胞的假设。 将在良性前列腺和CaP的短期人类异种移植物、TRAMP和CWR 22模型以及在雄激素剥夺治疗之前和期间获得的系列前列腺活检中检查基底细胞、血管内皮细胞和神经内分泌细胞在能够在相对雄激素缺乏下生长的CaP细胞群体的出现中的作用。

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.