Microtubule dependent AR signaling predicts taxane sensitivity

微管依赖性 AR 信号传导预测紫杉烷敏感性

• 批准号: 8073086
• 负责人: PARASKEVI GIANNAKAKOU
• 金额: $ 34.02万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073086
• 关键词: Ablation; Acetylation; Androgen Receptor; Androgen Response Element; Androgens; Antimitotic Agents; Antineoplastic Agents; Binding; Biology; Blood; Cancer Etiology; Cancer Model; Cancer Patient; Cause of Death; Cell Nucleus; Cell division; Cells; Cessation of life; Clinic; Clinical; Cytoplasm; Cytoskeleton; Data; Development; Diagnosis; Disease; Drug Binding Site; Drug Delivery Systems; Drug resistance; Dynein ATPase; Exhibits; Gene Targeting; Genes; Growth; Growth and Development function; Health; In Vitro; Interphase; Laboratories; Lead; Ligand Binding; Ligands; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Microtubules; Mitotic; Molecular; Motor; Mutation; Neoplasm Metastasis; Nuclear; Nuclear Receptors; Nuclear Translocation; PC3 cell line; Paclitaxel; Patients; Phenotype; Play; Pre-Clinical Model; Prostate; Prostate-Specific Antigen; Proteins; Receptor Signaling; Recurrence; Refractory; Research; Resistance; Role; Sampling; Second Primary Neoplasms; Signal Pathway; Signal Transduction; Taxane Compound; Therapeutic Intervention; Time; Toxic effect; Transcriptional Activation; Translations; Tubulin; United States; anticancer research; base; chemotherapy; deprivation; design; docetaxel; effective therapy; improved; male; men; neoplastic cell; novel; pre-clinical; receptor; receptor binding; response; standard of care; steroid hormone receptor; taxane; trafficking; transcription factor; tumor; tumor growth

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.

描述（由申请人提供）：前列腺癌是美国男性中最常诊断的恶性肿瘤，也是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通过雄激素受体（AR）起作用的雄激素。AR在前列腺癌的生物学和进展中起着如此重要的作用，以至于雄激素消融治疗在>50年后仍然是转移性前列腺癌的最有效治疗。然而，许多男性最终失败这种治疗和复发性去势难治性前列腺癌（CRPC）死亡。CRPC是前列腺癌的一种致命形式，其进展和转移。尽管雄激素剥夺，这种进展与活性雄激素受体（AR）信号通路相关。目前尚无有效的治疗方法，因此，抑制AR信号通路和靶基因转录激活的策略是前列腺癌研究的前沿。通过这个提议，我们表明紫杉烷类通过损害AR核转位和MT细胞骨架破坏下游的积累来抑制AR的转录活性。此外，我们的临床前数据清楚地将紫杉烷敏感性与致死表型存活转录因子AR的有效抑制联系起来。因此，我们认为紫杉醇治疗后这些转录因子的调节决定了临床反应.鉴于紫杉烷类最近已成为改善转移性CRPC生存率的第一类抗癌药物，目前代表了CRPC一线治疗的标准治疗，将这些临床前发现转化为临床环境将对PC目前的治疗方式产生巨大影响。因此，我们计划：具体目的1）在CRPC患者接受基于紫杉醇的治疗之前和之后从他们分离循环肿瘤细胞（CTC），以研究临床应答的分子基础。具体目的2）研究微管蛋白乙酰化在前列腺癌细胞株紫杉烷敏感性中的作用。3）在PC的临床前模型中研究紫杉烷介导的AR信号转导抑制的分子机制。我们的建议有望确定前列腺癌患者中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最多的患者子集，同时使患者免受紫杉烷化疗的毒性作用。临床上对药物耐药性的分子认识将导致治疗干预措施的确定，以克服it.Public健康相关性：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。我们发现紫杉烷通过损害AR核转位和MT细胞骨架破坏下游的积累抑制AR的转录活性，我们的临床前数据清楚地将紫杉烷敏感性与致死表型存活转录因子AR的有效抑制联系起来，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。鉴于紫杉烷类最近已成为改善转移性去势难治性前列腺癌（CRPC）生存率的第一类抗癌药物，目前代表CRPC一线治疗的标准治疗，将这些临床前发现转化为临床环境将对前列腺癌目前的治疗方式产生巨大影响。