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: 8266465
• 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/8266465
• 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; 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

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 activitation 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.

前列腺癌是最常诊断的恶性肿瘤，也是前列腺癌死亡的第二大原因。 癌症在美国的男性中。这是公认的正常发展和维护 前列腺的功能依赖于通过雄激素受体（AR）起作用的雄激素。AR扮演着如此核心的角色 在前列腺癌的生物学和进展中，雄激素消融治疗在> 50年后仍然存在， 治疗转移性前列腺癌最有效的方法然而，许多男性最终失败了这种治疗， 死于复发性去势难治性前列腺癌（CRPC）。CRPC是一种致命的前列腺癌， 进展和转移。尽管雄激素剥夺，但这种进展与活跃的 雄激素受体（AR）信号通路。目前，尚无有效的治疗方法。 因此，AR信号传导和靶基因的转录激活处于前列腺疾病研究的前沿。 癌通过这个提议，我们表明紫杉烷通过损害AR抑制AR的转录活性， 核移位和MT细胞骨架破坏下游的积累。而且我们的 临床前数据清楚地将紫杉烷敏感性与致死表型存活的有效抑制联系起来 转录因子AR。因此，我们提出，这些转录因子的调节后，紫杉醇- 治疗决定临床反应。鉴于紫杉烷类最近已成为第一类 提高转移性CRPC生存率的抗肿瘤药物，目前代表了 CRPC的一线治疗，这些临床前发现转化为临床环境将有巨大的 对PC目前治疗方式的影响。因此，我们计划： 具体目的1）在CRPC患者接受化疗之前和之后从他们分离循环肿瘤细胞（CTC）， 以紫杉醇为基础的治疗，以研究临床反应的分子基础。 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）研究紫杉烷介导的AR信号抑制的分子机制， PC的临床前模型 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最多的患者子集， 紫杉烷化疗的毒副作用临床上对耐药性的分子认识将 从而找出治疗性干预措施来克服它。