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 前列腺癌是在退伍军人癌症患者中最常见的癌症 每年有13,000名退伍军人被诊断出患有前列腺癌。耐铸造前列腺癌（CRPC）是 致命类型的前列腺癌类型是由于对雄激素剥夺疗法的抗性和新的 产生抗雄激素药物（即乙酸酯和enzalutamide）。因此，有一个紧急的 需要通过理解导致CRPC和 确定新的治疗靶标。 异常的Wnt/β-catenin信号传导在抗抗雄激素疗法的耐药性中起着至关重要的作用 CRPC。在我们的初步研究中，我们发现裂缝/机器人GTPase激活蛋白1（SRGAP1）是一个潜力 Wnt靶基因并由CRPC中的雄激素受体（AR）信号共同调节。此外，我们发现 狭缝/回旋处（ROBO）信号的多个组件，包括SRGAP1，ROBO1，SLIT2和RHOA，是 与主PCA相比，在CRPC中放大和过表达。 反之亦然，缝隙/机器人信号传导可以通过促进核来激活Wnt/β-catenin信号传导 β-catenin通过Rac1激活的定位。我们还发现SRGAP1与鸟嘌呤相互作用 已知可以调节的核苷酸vav2/vav3核苷酸交换因子（GEF）家族 雄激素受体变体7（AR V7和全长AR）以及CRPC细胞的存活。基于这些 观察结果，我们假设SRGAP1在通过倒数的进展中起着至关重要的作用 AR和WNT信号的扩增。 为了检验这些假设，我们将首先检验以下假设：SRGAP1是所需的下降之一 流中间体以进展为CRPC和抗抗雄激素疗法。第二，我们会的 评估SRGAP1对AR和Wnt/-catenin信号的功能和机理重要性以及 CRPC的生物行为。第三，我们将确定相互作用的病理生理相关性 缝隙/robo/srgap1，ar和wnt信号传导以及srgap1的表达是否将是一个很好的预测指标 CRPC患者的疾病进展和总体存活。 我们期望定义SRGAP1在CRPC中的作用和机制，这可能导致 鉴定新的靶标或预后标记，用于管理这种致命的肿瘤。所以， 我们提议的工作与VA部的优先研究领域非常吻合 - 资深人口和精确医学研究的医疗保健伯恩（Burnen）的重点是个人治疗 回复。