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: 8469008
• 负责人: PARASKEVI GIANNAKAKOU
• 金额: $ 31.97万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469008
• 关键词: Ablation; Acetylation; Androgen Receptor; Androgen Response Element; Androgens; Antimitotic Agents; Antineoplastic Agents; Binding; Biology; Blood; Cancer Etiology; 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 Targeting; 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 Circulating Cells; 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; novel; pre-clinical; prostate cancer model; 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.

前列腺癌是最常见的恶性肿瘤，也是导致死亡的第二大原因

项目成果

Androgen receptor on the move: boarding the microtubule expressway to the nucleus.

• DOI: 10.1158/0008-5472.can-12-0783
• 发表时间: 2012-09-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Thadani-Mulero M;Nanus DM;Giannakakou P
• 通讯作者: Giannakakou P

Functional characterization of circulating tumor cells with a prostate-cancer-specific microfluidic device.

• DOI: 10.1371/journal.pone.0035976
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kirby BJ;Jodari M;Loftus MS;Gakhar G;Pratt ED;Chanel-Vos C;Gleghorn JP;Santana SM;Liu H;Smith JP;Navarro VN;Tagawa ST;Bander NH;Nanus DM;Giannakakou P
• 通讯作者: Giannakakou P

Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer.

• DOI: 10.1158/0008-5472.can-11-1417
• 发表时间: 2011-09-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Darshan MS;Loftus MS;Thadani-Mulero M;Levy BP;Escuin D;Zhou XK;Gjyrezi A;Chanel-Vos C;Shen R;Tagawa ST;Bander NH;Nanus DM;Giannakakou P
• 通讯作者: Giannakakou P

Circulating tumor cells from prostate cancer patients interact with E-selectin under physiologic blood flow.

• DOI: 10.1371/journal.pone.0085143
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Gakhar G;Navarro VN;Jurish M;Lee GY;Tagawa ST;Akhtar NH;Seandel M;Geng Y;Liu H;Bander NH;Giannakakou P;Christos PJ;King MR;Nanus DM
• 通讯作者: Nanus DM