Prostate Cancer Health Disparity: Role of PDEF

前列腺癌健康差异：PDEF 的作用

• 批准号: 10689652
• 负责人: HARI K KOUL
• 金额: $ 32.95万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689652
• 关键词: Address; African American; Animal Model; Azacitidine; Behavior; Biological Models; Castration; Caucasians; Cell Culture Techniques; Cells; Clinical; Clinical Data; DNA; DNA Methylation; DNA Methyltransferase Inhibitor; Data; Data Set; Decitabine; Development; Disease; Disease Outcome; Early Diagnosis; Future; Genes; Genetic Transcription; Gleason Grade for Prostate Cancer; Goals; Growth; Indolent; Intervention; Invaded; Investigation; Knowledge; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Measurable; Measurement; Metastatic Prostate Cancer; Methods; Methylation; Micrometastasis; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Neoplasm Metastasis; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Prostate; Prostate Cancer therapy; Rectum; Resistance; Risk; Role; Sampling; Signal Transduction; Specimen; TWIST1 gene; Testing; Tissues; Transferase; Treatment outcome; United States National Institutes of Health; anticancer research; cancer health disparity; cell motility; conventional therapy; demethylation; digital; early onset; effective therapy; enzalutamide; epigenetic regulation; ethnic disparity; experimental study; health disparity; in vitro activity; in vivo; in vivo Model; inhibitor; innovation; knock-down; mRNA Expression; men; mortality; novel; patient stratification; prognostic indicator; promoter; prostate cancer cell; prostate cancer metastasis; protein expression; racial disparity; rectal; tibia; tool; transcription factor; tumor; tumor xenograft

In African American (AA) men prostate cancer is characterized by higher aggressiveness, more extensive metastases, early onset, and increased mortality rates compared to those in Caucasian men. We propose to evaluate role of PDEF (Prostate Derived Ets Factor) and TWIST-1 in PCa health disparity. The studies proposed in this application are driven by our novel observations that there is graded decrease in PDEF levels in prostate cancer cells with increasing aggressive phenotype and in prostate cancer tissue sections of patients. We also observed in multiple clinical data sets that PDEF mRNA expression is decreased in high Gleason grade PCa and in tumor metastasis. Moreover we observed a reciprocal relationship between PDEF and Twist-1 expression in PCa tissues and that PDEF and Twist-1 expression could predict PCa patient survival. In preliminary studies we observed that PDEF expression is decreased in prostate cancer cells from AA men and in cells with aggressive phenotype, and experimental modulation of PDEF expression modulates cell migration and clonogenic activity in part by promoting luminal differentiation. These exciting preliminary data form the basis of our proposed hypothesis: First, that, “ In African American Men PDEF could serve as a functional marker for distinguishing aggressive prostate cancer from an indolent disease.” Second that “PDEF functions as a metastasis suppressor in prostate cancer in part by modulating expression of Twist-1”, and third that “Loss of PDEF can help us stratify PCa patients that might respond to DNA methyl transferase inhibitors”. We propose three aims to test these hypothesis. AIM 1: To establish differences in expression levels of PDEF between grade-matched Prostate Cancer specimens from African American and Caucasian men and correlate these with patient outcomes; AIM 2: To determine the role of PDEF in PCa metastasis and racial disparity using in vivo model systems, and ; *AIM 3: To evaluate if prostate cancers with PDEF loss respond more favorably to combination of ADT (Enzalutamide) and DNA methyl-transferase inhibitors (azacytidine and decitabine) as compared to ATD alone. The proposed studies are innovative as these will enhance understanding of role of PDEF in suppressing prostate cancer metastasis and help us evaluate usefulness of PDEF/Twist-1 in early detection of patients that may harbor aggressive prostate cancer with enhanced metastatic potential. The impact of our study will be on the development of a new method to distinguish aggressive and metastatic phenotype of prostate cancer from an indolent disease, which will particularly benefit AA men, and reduce ethnic disparity in in prostate cancer treatment outcomes.

在非洲裔美国人（AA）男性中，前列腺癌的特征是侵袭性更强，更广泛， 与白人男性相比，转移、早发和死亡率增加。我们建议 评估PDEF（前列腺衍生Ets因子）和TWIST-1在PCa健康差异中的作用。研究 在本申请中提出的是由我们的新观察结果驱动的，即PDEF水平有分级下降 在具有增加的侵袭性表型的前列腺癌细胞中和在具有增加的侵袭性表型的前列腺癌组织切片中， 患者我们还在多个临床数据集中观察到，PDEF mRNA表达在高表达组中降低， Gleason分级PCa和肿瘤转移。此外，我们观察到PDEF之间的相互关系 PDEF和Twist-1的表达可预测PCa患者的预后 生存在初步研究中，我们观察到PDEF表达在前列腺癌细胞中减少， AA男性和具有侵袭性表型的细胞中，以及PDEF表达调节的实验调节 细胞迁移和克隆形成活性部分通过促进管腔分化。这些令人兴奋的初步 数据构成了我们提出的假设的基础：首先，“在非洲裔美国人中，PDEF可以作为一种 用于区分侵袭性前列腺癌和惰性疾病的功能标记。第二，“十年方案” 在前列腺癌中部分通过调节Twist-1”的表达作为转移抑制因子发挥作用， “PDEF的缺失可以帮助我们对可能对DNA甲基转移酶抑制剂有反应的PCa患者进行分层”。 我们提出了三个目标来检验这些假设。目的1：确定PDEF表达水平的差异 非裔美国人和白人男性的等级匹配前列腺癌标本之间的差异及其相关性 目的2：确定PDEF在PCa转移和种族差异中的作用 使用体内模型系统，以及; * 目的3：评估PDEF缺失的前列腺癌是否对PDEF缺失的反应更大。 优选ADT（恩杂鲁胺）和DNA甲基转移酶抑制剂（氮杂胞苷和 地西他滨）与单独的ATD相比。拟议的研究是创新的，因为这些研究将提高 了解PDEF在抑制前列腺癌转移中的作用，并帮助我们评估 PDEF/Twist-1在早期检测可能具有增强的侵袭性前列腺癌患者中的应用 转移潜能我们的研究将对发展一种新的区分方法产生影响 前列腺癌的侵袭性和转移性表型来自惰性疾病， 有益于AA男性，并减少前列腺癌治疗结果的种族差异。

项目成果

Hippo pathway: Regulation, deregulation and potential therapeutic targets in cancer.

• DOI: 10.1016/j.canlet.2021.03.006
• 发表时间: 2021-06-01
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Mohajan, Suman;Jaiswal, Praveen Kumar;Vatanmakarian, Mousa;Yousefi, Hassan;Sankaralingam, Saikolappan;Alahari, Suresh K.;Koul, Sweaty;Koul, Hari K.
• 通讯作者: Koul, Hari K.

Regulation of SPDEF expression by DNA methylation in advanced prostate cancer.

• DOI: 10.3389/fendo.2023.1156120
• 发表时间: 2023
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2