Role of Axl in docetaxel resistance in prostate cancer

Axl 在前列腺癌多西紫杉醇耐药中的作用

• 批准号: 8880713
• 负责人: TOWIA A. LIBERMANN
• 金额: $ 21.11万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-12 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8880713
• 关键词: Ablation; Androgen Receptor; Androgens; Apoptosis; Automobile Driving; Cancer Patient; Cells; Cisplatin; Combined Modality Therapy; Data; Development; Dose; Drug Kinetics; Drug resistance; Drug usage; Epithelial; Erlotinib; Evaluation; Functional disorder; Gene Expression Profile; Generations; Health; Imatinib; Investigation; Lead; Life Expectancy; Link; MAP Kinase Gene; MAP Kinase Signaling Pathways; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mesenchymal; Metastatic Prostate Cancer; Mitogen-Activated Protein Kinases; Molecular; Pathology; Pathway interactions; Patients; Play; Proteins; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Resistance; Resistance development; Role; SCID Mice; Signal Pathway; Signal Transduction; Staging; Systems Biology; Taxane Compound; Testing; Therapeutic; Treatment Efficacy; Up-Regulation; Xenograft procedure; axl receptor tyrosine kinase; cancer therapy; cancer type; castration resistant prostate cancer; design; docetaxel; effective therapy; hormone refractory prostate cancer; in vivo; inhibitor/antagonist; innovation; migration; novel; novel strategies; novel therapeutics; outcome forecast; overexpression; pre-clinical; prevent; prostate cancer cell; prostate cancer cell line; prostate cancer model; response; taxane; therapy resistant; tumor

DESCRIPTION (provided by applicant): While there has been significant progress in management of early stages of prostate cancer (PCa), metastatic hormone-refractory PCa has few effective therapeutic strategies available. Docetaxel, the main chemotherapeutic drug used in aggressive prostate cancer treatment, has shown limited efficacy against metastatic PCa, primarily due to invariable development of drug resistance, necessitating a thorough investigation of the mechanisms underlying this drug resistance and the development of novel, more efficacious therapies to prevent or overcome resistance. The receptor tyrosine kinase Axl has been implicated in the pathology of many cancers, including advanced PCa. In addition, upregulation of Axl has been linked to poor prognosis and resistance to therapy in several cancer types. We are now providing preliminary evidence that Axl is the key driver of resistance to docetaxel in PCa. While knockdown of Axl as well as Axl blockage by a pharmacologic Axl inhibitor sensitizes PCa cells to docetaxel, Axl overexpression reduces docetaxel efficacy in PCa cells. Moreover, we demonstrate that generation of docetaxel-resistant PCa cells results in upregulation of Axl expression, corroborating our notion that Axl plays a critical role in docetaxe resistance. We will, thus, test our hypothesis that Axl activation leads to resistance to docetaxel therapy in PCa and that inhibition of Axl will overcome, delay or prevent resistance to docetaxel in PCa. In order to decipher the precise role of Axl in docetaxel resistance and to develop a novel therapeutic strategy for advanced PCa we will, therefore, define the relevance of Axl expression/activity in docetaxel and cabazitaxel resistant PCa cells and perform a preclinical assessment of Axl inhibition to prevent, delay or overcome docetaxel resistance in androgen receptor-positive, androgen responsive and castration-resistant PCa xenografts. Detailed mechanistic analysis of Axl signaling in docetaxel-resistance will determine whether Axl-mediated activation of NF-κB and MAP kinase signaling pathways is critical for inducing escape from docetaxel response. In Specific Aim 1 we will evaluate the effects of docetaxel treatment on proliferation, migration, invasion, and apoptosis of docetaxel resistant PCa cell lines lacking Axl expression. Furthermore, we will evaluate co-treatment of cells with the Axl inhibitors and docetaxel as well as pre-treatment with Axl inhibitors in order to determine if the use of Axl inhibitors sensitizes cells to docetaxel. In Specific Aim 2 preclinical in vivo assessment of docetaxel-resistant PCa xenografts will determine whether knockdown of Axl or pharmacological, targeted Axl inhibition is able to prevent, delay or overcome docetaxel resistance and enhances anti-tumor efficacy of docetaxel. Specific Aim 3 will decipher the precise molecular mechanisms and signaling pathways involved in Axl regulation of drug resistance, with an initial focus on the NF-κB and MAPK cascades and androgen signaling. The proposed study of Axl as a driver of docetaxel and cabazitaxel resistance in PCa is anticipated to lead to an innovative combination therapy approach for a more effective treatment of metastatic PCa.

描述（由申请人提供）：虽然在前列腺癌（PCa）早期阶段的治疗方面取得了重大进展，但转移性激素难治性 PCa 几乎没有可用的有效治疗策略，多西紫杉醇是用于侵袭性前列腺癌治疗的主要化疗药物。对转移性 PCa 的疗效有限，主要是由于耐药性的不断发展，因此需要彻底研究这种耐药性背后的机制，并开发新的、更有效的疗法来预防或治疗。受体酪氨酸激酶 Axl 与许多癌症的病理学有关，包括晚期 PCa。此外，Axl 的上调与多种癌症类型的不良预后和治疗耐药有关。 Axl 是 PCa 中多西紫杉醇耐药的关键驱动因素，而药理学 Axl 抑制剂敲低 Axl 以及 Axl 阻断会使 PCa 细胞对多西紫杉醇敏感，但 Axl 过度表达。此外，我们证明多西紫杉醇耐药性 PCa 细胞的产生会导致 Axl 表达上调，证实了我们的观点，即 Axl 在多西紫杉醇耐药中发挥着关键作用，因此，我们将检验我们的假设，即 Axl 激活。导致对多西紫杉醇产生耐药性 治疗 PCa 和抑制 Axl 将克服、延迟或预防 PCa 对多西他赛的耐药性。因此，为了破译 Axl 在多西他赛耐药中的确切作用，并开发一种针对晚期 PCa 的新治疗策略，我们将定义其相关性。多西他赛和卡巴他赛耐药 PCa 细胞中的 Axl 表达/活性，并对 Axl 抑制进行临床前评估，以预防、延迟或克服雄激素受体阳性、雄激素反应性和去势抵抗性 PCa 异种移植物对多西紫杉醇耐药的 Axl 信号传导的详细机制分析将确定 Axl 介导的 NF-κB 和 MAP 激酶信号通路激活是否对于诱导逃避多西紫杉醇反应至关重要。评估多西紫杉醇治疗对缺乏 Axl 表达的多西紫杉醇耐药 PCa 细胞系的增殖、迁移、侵袭和凋亡的影响此外，我们将评估。使用 Axl 抑制剂和多西紫杉醇共同处理细胞以及用 Axl 抑制剂进行预处理，以确定使用 Axl 抑制剂是否会使细胞对多西紫杉醇敏感。在特定目标 2 中，对多西紫杉醇耐药的 PCa 异种移植物进行临床前体内评估。确定 Axl 敲低或药理学靶向 Axl 抑制是否能够预防、延迟或克服多西紫杉醇耐药性并增强抗肿瘤功效具体目标 3 将破译 Axl 耐药性调节所涉及的精确分子机制和信号通路，最初重点关注 NF-κB 和 MAPK 级联以及雄激素信号传导。 PCa 的耐药性预计将带来一种创新的联合治疗方法，以更有效地治疗转移性 PCa。