Therapeutic targeting Wnt5A signaling for advanced prostate cancer

靶向 Wnt5A 信号传导治疗晚期前列腺癌

基本信息

批准号：
10526399
负责人：
Allen C Gao
金额：
$ 37.4万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/10526399
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 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

项目摘要

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.

恩扎拉胺和阿比特龙最初对治疗持cast割前列腺癌的治疗有效（CRPC）。但是，对这两种药物的抗性经常通过不完全的机制发生理解。来自临床和实验研究的证据表明，Wnt信号，特别是通过WNT5A，在促进CRPC进程和抗耐药性诱导中起着至关重要的作用和阿比罗酮。迫切需要制定针对WNT5A以克服抵抗力的新型策略。初步和临床数据表明，Wnt5a信号在耐药性CRPC细胞中显着激活和CRPC患者的标本。 Wnt5a的下调调节抑制AR/AR变体表达，抑制细胞生长，并对抗雄激素治疗的抗性细胞敏感。该提议的目的是完全描述Wnt5a信号在耐药性中的作用，并使用两个确定靶向Wnt5a的功效克服抵抗的新型策略。在AIM 1中，我们将确定Wnt5a在开发中的作用对恩扎拉胺和阿比罗酮的抗性。在AIM 2中，我们将评估两种新型策略的功效靶向WNT5A抑制抗性CRPC肿瘤的生长并重新敏感到enzalutamide/abiraterone 治疗。在AIM 3中，我们将通过抗性CRPC中的Wnt5a抑制来阐明作用机理。我们希望通过完成这项研究，我们将提供一种新型的治疗方法，以通过定位WNT5A。我们还期望将WNT5A与Enzalutamide/Abiraterone疗法结合使用增加第二代抗雄激素益处的幅度和持续时间。