A novel targetable mechanism for castration-resistant prostate cancer

去势抵抗性前列腺癌的新型靶向机制

• 批准号: 10513281
• 负责人: Xiaolin Zi
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513281
• 关键词: Acetates; Affect; Androgen Antagonists; Androgen Receptor; Androgens; Antiandrogen Therapy; Area; Behavior; Benign Prostatic Hypertrophy; Binding; Biological; Biological Assay; Biological Markers; Cancer Patient; Carcinoma; Databases; Diagnosis; Disease; Disease Progression; Early Detection Research Network; Family; Fibroblasts; GTPase-Activating Proteins; Generations; Genes; Genetic Transcription; Growth; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Healthcare; Human; Immunohistochemistry; Individual; Invaded; Length; Link; Luciferases; Malignant neoplasm of prostate; Medical center; Neoplasm Metastasis; Neoplasms; Nuclear; Oncogenes; Patients; Pharmaceutical Preparations; Play; Prognosis; Prognostic Marker; Prostate; Radical Prostatectomy; Receptor Signaling; Regulation; Reporter; Research Priority; Resistance; Resistance development; Resources; Role; SCID Mice; Signal Transduction; Specimen; Testing; Tissue Microarray; Tissues; United States Department of Veterans Affairs; Variant; Veterans; WNT Signaling Pathway; Work; Xenograft Model; abiraterone; androgen deprivation therapy; androgen sensitive; beta catenin; cancer diagnosis; care burden; castration resistant prostate cancer; chromatin immunoprecipitation; cohort; deprivation; enzalutamide; follow-up; implantation; in silico; in vivo; lymphoid enhancer-binding factor 1; migration; military veteran; mutant; new therapeutic target; novel; novel strategies; overexpression; palliative; precision medicine; programs; promoter; prostate cancer cell; prostate cancer cell line; prostate cancer metastasis; prostate cancer progression; prostate transurethral resection; rho GTPase-activating protein; small hairpin RNA; transdifferentiation; treatment response; tumor; tumorigenesis

Project Summary Prostate cancer is the most frequently diagnosed cancer among veteran cancer patients with more than 13,000 veterans diagnosed with prostate cancer each year. Castration-resistant prostate cancer (CRPC) is a lethal type of prostate cancer due to developing resistance to androgen deprivation therapy and the new generation of anti-androgen drugs (i.e. Abiraterone Acetate, and Enzalutamide). Therefore, there is an urgent need to develop novel approaches for treatment of CRPC by understanding mechanisms leading to CRPC and identifying new therapeutic targets. Aberrant Wnt/β-catenin signaling plays a critical role in resistance to anti-androgen therapies and in CRPC. In our preliminary studies, we found that Slit/Robo GTPase activating protein 1 (srGAP1) is a potential Wnt target gene and co-regulated by androgen receptor (AR) signaling in CRPC. In addition, we found that multiple components of Slit/Roundabout (Robo) signaling, including srGAP1, Robo1, Slit2 and RhoA, are amplified and overexpressed in CRPC compared to primary PCa. Vice versa, Slit/Robo signaling can activate Wnt/β-catenin signaling by promoting the nuclear localization of β-catenin via Rac1 activation. We have also discovered that srGAP1 interacts with guanine nucleotide exchange factor (GEF) family of oncogenes Vav2/Vav3 that are known to regulate nuclear levels of androgen receptor variant 7 (AR V7 and full-length AR) and the survival of CRPC cells. Based these observations, we hypothesize that srGAP1 plays a critical role in progression to CRPC through reciprocal amplification of both AR and Wnt signaling. To test these hypotheses, we will first test the hypothesis that srGAP1 is one of the required down- stream intermediates for progression to CRPC and for resistance to anti-androgen therapies. Second, we will assess the functional and mechanistic importance of srGAP1 on AR and Wnt/-catenin signaling and on biological behaviors of CRPC. Third, we will determine pathophysiological relevance of the interplay between Slit/Robo/srGAP1, AR and Wnt signaling and whether the expression of srGAP1 will be a good predictor for disease progression and overall survival of CRPC patients. We expect to define the role and mechanisms of srGAP1 in progression to CRPC, which may lead to identification of a novel target or prognostic markers for the management of this deadly neoplasm. Therefore, our proposed work aligns very well with priority research areas of the Department of VA---Diseases with a high healthcare burden in the Veteran population and Precision medicine studies focused on individual treatment response.

项目摘要 前列腺癌是老年癌症患者中最常被诊断出的癌症，年龄超过 每年有13,000名退伍军人被诊断出患有前列腺癌。耐去势前列腺癌(CRPC)是 雄激素剥夺治疗耐药所致的致死型前列腺癌及其新疗法 产生的抗雄激素药物(即，阿比拉酮和恩扎鲁胺)。因此，当务之急是 需要通过了解导致CRPC和CRPC的机制来开发治疗CRPC的新方法 确定新的治疗靶点。 Wnt/β-catenin信号通路异常在抗雄激素治疗耐药中起关键作用 CRPC。在我们的初步研究中，我们发现Sit/Robo GTP酶激活蛋白1(SrGAP1)是一个潜在的 WNT靶基因和雄激素受体(AR)信号在CRPC中的共同调控。另外，我们发现， 缝隙/环形交叉口(ROBO)信令的多个组件，包括srGAP1、Robo1、Slit2和RhoA， 与原发PCa相比，CRPC中扩增和过表达。 反之亦然，Sit/Robo信号通路可通过促进核转录激活Wnt/β-catenin信号通路 β-连环蛋白通过Rac1激活定位。我们还发现srGAP1与鸟嘌呤相互作用 核苷酸交换因子家族的癌基因Vav2/Vav3，已知调节细胞核水平。 雄激素受体变异体7(AR V7和全长AR)与CRPC细胞的存活。基于这些 ，我们假设srGAP1通过相互作用在CRPC的进展中起关键作用。 AR和Wnt信号的扩增。 为了检验这些假设，我们将首先检验srGAP1是必需的down- 向CRPC进展和抗雄激素治疗耐药的流动中间体。第二，我们将 评估srGAP1在AR和Wnt/-catenin信号和ON中的功能和机制重要性 CRPC的生物学行为。第三，我们将确定相互作用的病理生理学相关性 Sit/Robo/srGAP1、AR和Wnt信号转导以及srGAP1的表达是否可以作为预测 慢性前列腺癌患者的疾病进展和总存活率。 我们希望确定srGAP1在向CRPC发展过程中的作用和机制，这可能导致 寻找治疗这种致命肿瘤的新靶点或预后标记物。因此， 我们建议的工作非常符合退伍军人事务部的优先研究领域-疾病与高 退伍军人群体的医疗负担和专注于个体化治疗的精准医学研究 回应。