Racial Disparity in the Expression of Androgen Receptor Splice Variants (AR-SVs) in Prostate Cancer

前列腺癌中雄激素受体剪接变体 (AR-SV) 表达的种族差异

基本信息

批准号：
10099535
负责人：
Ramesh Narayanan
金额：
$ 22.8万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
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：
2020-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10099535
关键词：
Address African American Aftercare Age Androgen Receptor Androgens Animal Care and Use Committees Antibodies Binding CYP17A1 gene Cancer Patient Cancer Relapse Caucasians Clinical Clinical Trials Competitive Binding Custom Data Development Diagnosis Disease-Free Survival Failure Formalin Frequencies Future Gene Expression Profile Genes Gleason Grade for Prostate Cancer Healthcare Hospitals Incidence Insurance Ligand Binding Domain Malignant neoplasm of prostate Methodist Church Mus PSA level Paraffin Embedding Pathology Patients Pharmaceutical Preparations Phenotype Population Prognostic Marker Progression-Free Survivals Property Prostate Cancer therapy Prostatic Intraepithelial Neoplasias Protocols documentation RNA Splicing Race Research Personnel Resistance development Sampling Screening for Prostate Cancer Slide Specimen Stains Symptoms Tennessee Testing Therapeutic Tissue Banks Tissue Sample Tissues Treatment Failure United States Universities Variant Xenograft procedure abiraterone advanced prostate cancer aged anticancer research cancer diagnosis castration resistant prostate cancer caucasian American drug development efficacy testing experience genetic signature inhibitor/antagonist man men nano-string next generation sequencing novel outcome forecast prevent prostate cancer survivors protocol development racial difference racial disparity screening therapy development tumor

项目摘要

Approximately 174,000 men in the United States were diagnosed with prostate cancer (PCa) and approximately 31,000 died of PCa in 2019. The number of PCa survivors is expected to increase from 3.3 million men currently to 4.5 million by 2026. One of the primary reasons for treatment failure and castration-resistant prostate cancer (CRPC) relapse is expression of constitutively-active AR splice variants (AR-SVs) that lack the ligand binding domain (LBD) and thus remain constitutively active. AR-SVs contribute to an aggressive phenotype of CRPC, shorter progression-free survival (PFS), and failure to respond to enzalutamide or abiraterone. Compared to Caucasian men, African American men have a 63% higher overall PCa incidence (228.8 vs 140.3 per 100,000, age adjusted to 2000 US population). These patients are more likely to be diagnosed with aggressive/potentially lethal PCa, are 2.44-fold more likely to die from PCa and have shorter disease-free survival. Our central hypothesis is that the higher incidence of aggressive CRPC in African American men is due to the higher expression and function of AR-SVs compared to their Caucasian counterparts. As our SARDs are the only set of molecules having the properties to degrade the AR-SVs, proving this hypothesis will help us to tailor our drug development protocols towards the African American men who might have higher expression of AR-SVs. To address the hypothesis that the African American men express AR-SVs at a higher level than Caucasian men, we will determine the expression of AR-V7 in PCa and CRPC specimens from African American and Caucasian men (specific aim-1), determine race differences in AR-V7 function by quantifying AR-V7-target gene signature expression in PCa tissue from African American and Caucasian PCa patients (specific aim-2), and test the efficacy of SARDs in CRPC patient-derived xenograft UT-1335 that was obtained from an African American man (specific aim-3). The data will be a harbinger for future drug development tailored towards African American men with PCa.

美国约有174,000名男性被诊断出患有前列腺癌（PCA），大约 2019年有31,000人死于PCA。预计PCA幸存者的数量将从目前的330万人增加到2026年为450万。治疗衰竭和cast割前列腺癌的主要原因之一（CRPC）复发是缺乏配体结合的组成型AR剪接变体（AR-SVS）的表达域（LBD），因此保持组成性活跃。 AR-SVS有助于CRPC的积极表型，较短的无进展生存期（PFS），未能对enzalutamide或abiraterone做出反应。相比高加索男性，非裔美国人的总体PCA发病率高63％（228.8 vs 140.3，每100,000，年龄调整为2000年美国人口）。这些患者更有可能被诊断出具有侵略性/潜在的患者致命的PCA，死于PCA的可能性更高，并且无病生存期更短。我们的中心假设是，非洲裔美国男性侵略性CRPC的发病率较高是由于较高 AR-SVS的表达和功能与它们的高加索对应物相比。因为我们的撒特是唯一的具有降解AR-SV的特性的一组分子，证明这一假设将有助于我们量身定制药物开发方案对可能具有更高表达AR-SV的非裔美国人。解决非洲裔美国人在高加索人高度表达AR-SVS的假设男士，我们将确定非裔美国人和来自非裔美国人和CRPC标本中AR-V7的表达高加索男性（特定AIM-1），通过量化AR-V7目标基因来确定AR-V7功能的种族差异来自非裔美国人和高加索PCA患者的PCA组织中的签名表达（特定AIM-2），并测试 SARD在CRPC患者衍生的异种移植物UT-1335中的功效是从非裔美国人获得的人（特定的AIM-3）。这些数据将是针对非裔美国人量身定制药物开发的预兆男士有PCA。