Therapeutic targeting Wnt5A signaling for advanced prostate cancer

靶向 Wnt5A 信号传导治疗晚期前列腺癌

• 批准号: 10310519
• 负责人: Allen C Gao
• 金额: $ 37.72万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10310519
• 关键词: Androgen Antagonists; Antiandrogen Therapy; Biological Availability; Biomedical Engineering; Cancer Patient; Cells; Chronic; Clinical Data; Clinical Research; Data; Development; Disease; Down-Regulation; Drug resistance; Future; Generations; Goals; Growth; In Vitro; Knowledge; LNCaP; Malignant neoplasm of prostate; Mediating; Metastatic Neoplasm to the Bone; Modeling; Patients; Pharmaceutical Preparations; Play; RNA; Resistance; Resistance development; Role; Signal Transduction; Small Interfering RNA; Specimen; System; Testing; Tissues; Toxic effect; Transfer RNA; Translating; Up-Regulation; Variant; WNT Signaling Pathway; abiraterone; advanced prostate cancer; base; carcinogenesis; castration resistant prostate cancer; cell growth; clinical development; effective therapy; efficacy evaluation; enzalutamide; experimental study; in vivo; inducible gene expression; inhibitor; knock-down; next generation; novel; novel strategies; novel therapeutic intervention; prostate cancer cell; prostate cancer progression; small molecule inhibitor; therapeutic target; therapy resistant; treatment strategy; tumor; tumor growth; tumor xenograft

Enzalutamide and abiraterone are initially effective for the treatment of castration-resistant prostate cancer (CRPC). However, resistance to both drugs occurs frequently through mechanisms which are incompletely understood. Evidence from both clinical and experimental studies demonstrate that Wnt signaling, particularly through Wnt5A, plays vital roles in promoting CRPC progression and induction of resistance to enzalutamide and abiraterone. Development of novel strategies targeting Wnt5A to overcome resistance is an urgent need. Preliminary and clinical data demonstrate that Wnt5A signaling is significantly activated in resistant CRPC cells and specimens from CRPC patients. Down regulation of Wnt5A inhibits AR/AR variants expression, suppresses cell growth, and resensitizes resistant cells to anti-androgen treatment. The objective of this proposal is to fully delineate the role of Wnt5A signaling in drug resistance and determine the efficacy of targeting Wnt5A using two novel strategies to overcome resistance. In Aim 1, we will determine the role of Wnt5A in the development of resistance to enzalutamide and abiraterone. In aim 2, we will evaluate the efficacy of two novel strategies targeting Wnt5A for inhibiting resistant CRPC tumor growth and re-sensitization to enzalutamide/abiraterone treatment. In aim 3, we will elucidate the mechanisms of action by Wnt5A inhibition in resistant CRPC. We hope that by completion of this study we will provide a novel therapeutic approach to treat advanced CRPC through targeting Wnt5A. We also expect that targeting Wnt5A in conjunction with enzalutamide/abiraterone therapy will increase the magnitude and duration of the benefits of second-generation antiandrogens.

Enzalutamide和阿比特龙对去势抵抗性前列腺癌的治疗最初有效 （CRPC）。然而，对这两种药物的耐药性经常通过不完全解释的机制发生。 明白来自临床和实验研究的证据表明，Wnt信号，特别是 通过Wnt 5A，在促进CRPC进展和诱导Enzalutamide耐药方面发挥重要作用 和阿比特龙。迫切需要开发靶向Wnt 5A以克服抗性的新策略。 初步和临床数据表明，Wnt 5A信号传导在耐药CRPC细胞中被显著激活 和CRPC患者的标本。下调Wnt 5A抑制AR/AR变体表达，抑制 细胞生长，并使抗性细胞对抗雄激素治疗重新敏感。这项建议的目的是充分 描述Wnt 5A信号传导在耐药性中的作用，并确定使用两种靶向Wnt 5A的有效性。 克服阻力的新策略。在目标1中，我们将确定Wnt 5A在以下发展中的作用： 对恩杂鲁胺和阿比特龙耐药。在目标2中，我们将评估两种新策略的有效性 靶向Wnt 5A以抑制耐药CRPC肿瘤生长和对恩杂鲁胺/阿比特龙的再致敏 治疗在目标3中，我们将阐明Wnt 5A抑制在耐药CRPC中的作用机制。我们希望 通过完成这项研究，我们将提供一种新的治疗方法来治疗晚期CRPC， 靶向Wnt 5A。我们还预计靶向Wnt 5A与恩杂鲁胺/阿比特龙治疗联合将 增加第二代抗雄激素的益处的幅度和持续时间。