Microtubule dependent AR signaling predicts taxane sensitivity

描述（由申请人提供）：前列腺癌是最常见的恶性肿瘤，也是美国男性癌症死亡的第二大原因。众所周知，前列腺的正常发育和维持依赖于雄激素通过雄激素受体（雄激素受体）起作用。AR在前列腺癌的生物学和进展中起着如此重要的作用，雄激素消融治疗在50年后仍然是转移性前列腺癌最有效的治疗方法。然而，许多男性最终无法接受这种治疗，并死于复发性去势难治性前列腺癌（CRPC）。CRPC是一种进展和转移的致死性前列腺癌。尽管雄激素剥夺，这种进展与活跃的雄激素受体（AR）信号通路有关。目前尚无有效的治疗方法。因此，抑制AR信号和靶基因转录激活的策略是前列腺癌研究的前沿。通过这一提议，我们表明紫杉烷通过破坏MT细胞骨架下游的AR核易位和积累来抑制AR的转录活性。此外，我们的临床前数据清楚地将紫杉醇敏感性与致命表型存活转录因子AR的有效抑制联系起来。因此，我们提出紫杉醇治疗后这些转录因子的调节决定了临床反应。鉴于紫杉烷最近成为提高转移性CRPC生存率的第一类抗肿瘤药物，目前代表了CRPC一线治疗的护理标准，将这些临床前研究结果转化为临床环境将对目前治疗PC的方式产生巨大影响。因此，我们计划：1)从CRPC患者接受多西他赛治疗前后分离循环肿瘤细胞（CTCs），以研究临床反应的分子基础。2)研究微管蛋白乙酰化在前列腺癌细胞紫杉烷敏感性中的作用。3)在临床前PC模型中研究紫杉烷介导的AR信号抑制的分子机制。我们的建议有望确定前列腺癌患者紫杉烷反应的分子决定因素，并帮助确定最有可能从这种治疗中获益的患者亚群，同时使患者免受紫杉烷化疗的毒性作用。在临床中对耐药性的分子认识将导致确定治疗干预措施来克服它。公共卫生相关性：抑制雄激素受体（AR）信号传导和靶基因转录激活的策略是前列腺癌研究的前沿，特别是对于死于复发性去势难治性前列腺癌（CRPC）的患者。我们在这里表明，紫杉烷通过损害AR核易位和MT细胞骨架破坏下游的积累来抑制AR的转录活性，我们的临床前数据清楚地将紫杉烷的敏感性与有效抑制致死-表型-存活转录因子AR联系起来，从而表明紫杉醇治疗后这些转录因子的调节决定了临床反应。鉴于紫杉烷最近成为提高转移性去极难治性前列腺癌（CRPC）生存率的第一类抗肿瘤药物，目前代表着CRPC一线治疗的护理标准，将这些临床前研究结果转化为临床环境将对目前前列腺癌的治疗方式产生巨大影响。

DESCRIPTION (provided by applicant): Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of death from cancer among males in the United States. It is well established that the normal development and maintenance of prostate is dependent on androgen acting through the androgen receptor (AR). AR plays such a central role in the biology and progression of prostate cancer, that androgen ablation therapy remains after >50 years the most effective treatment for metastatic prostate cancer. However, many men eventually fail this therapy and die of recurrent castrate-refractory prostate cancer (CRPC). CRPC is a lethal form of prostate cancer that progresses and metastasizes. This progression despite androgen deprivation is associated with an active androgen receptor (AR) - signaling pathway. At present, there is no effective therapy for it. Strategies to inhibit AR signaling and transcriptional activation of target genes are thus, at the forefront of research in prostate cancer. With this proposal we show that the taxanes inhibit the transcriptional activity of AR, by impairing AR nuclear translocation and accumulation downstream of disruption of the MT cytoskeleton. Furthermore, our preclinical data clearly link taxane sensitivity to the effective inhibition of the lethal-phenotype-survival transcription factor AR. Thus, we propose that modulation of these transcription factors following Taxol- treatment determines clinical response. Given that the taxanes have recently emerged as the first class of antineoplastic agents to improve survival for metastatic CRPC, currently representing the standard of care for first-line treatment of CRPC, translation of these preclinical findings into the clinical setting will have a huge impact on the way PC is currently treated. Thus we plan to: Specific Aim 1) Isolate circulating tumor cells (CTCs) from CRPC patients both before and after they receive docetaxel-based therapy in order to investigate the molecular basis of clinical response. Specific Aim 2) Investigate the role of tubulin acetylation in taxane sensitivity in prostate cancer cell lines. Specific Aim 3) Investigate the molecular mechanisms underlying taxane-mediated inhibition of AR signaling in preclinical models of PC. Our proposal promises to identify the molecular determinants of taxane response in prostate cancer patients and help identify the subset of patients most likely to benefit the most from this treatment while sparing patients from the toxic effects of taxane-chemotherapy. Molecular understanding of drug-resistance in the clinic will lead to the identification of therapeutic interventions to overcome it. PUBLIC HEALTH RELEVANCE: Strategies to inhibit androgen receptor (AR) signaling and transcriptional activation of target genes are at the forefront of research in prostate cancer, particularly for patients that die of recurrent castrate-refractory prostate cancer (CRPC). We show here that the taxanes inhibit the transcriptional activity of AR, by impairing AR nuclear translocation and accumulation downstream of disruption of the MT cytoskeleton and our preclinical data clearly link taxane sensitivity to the effective inhibition of the lethal-phenotype-survival transcription factor AR, thus suggesting that modulation of these transcription factors following Taxol treatment determines clinical response. Given that the taxanes have recently emerged as the first class of antineoplastic agents to improve survival for metastatic castrate-refractory prostate cancer (CRPC), currently representing the standard of care for first-line treatment of CRPC, translation of these preclinical findings into the clinical setting will have a huge impact on the way prostate cancer is currently treated.