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.

在非裔美国人 (AA) 男性中，前列腺癌的特点是侵袭性更高、范围更广 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 本申请中提出的建议是由我们的新观察结果驱动的，即 PDEF 水平逐渐下降 在具有增加侵袭性表型的前列腺癌细胞和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 表达在高浓度下降低。 格里森级 PCa 和肿瘤转移。此外，我们观察到 PDEF 之间存在相互关系。 和 Twist-1 在 PCa 组织中的表达，PDEF 和 Twist-1 表达可以预测 PCa 患者 生存。在初步研究中，我们观察到前列腺癌细胞中 PDEF 表达降低 AA 男性和具有攻击性表型的细胞中，PDEF 表达的实验调节 细胞迁移和克隆形成活性部分是通过促进管腔分化来实现的。这些激动人心的预赛 数据构成了我们提出的假设的基础：首先，“在非裔美国男性中，PDEF 可以作为 用于区分侵袭性前列腺癌和惰性疾病的功能标记。”其次，“PDF 部分通过调节 Twist-1 的表达在前列腺癌中发挥转移抑制作用”，第三 “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”。 我们提出三个目标来检验这些假设。目标 1：确定 PDEF 表达水平的差异 在非裔美国人和白人男性的等级匹配前列腺癌标本之间进行关联 这些与患者的结果有关；目标 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，并且； *目标 3：评估 PDEF 缺失的前列腺癌是否有更好的反应 有利于ADT（恩杂鲁胺）和DNA甲基转移酶抑制剂（氮胞苷和 地西他滨）与单独使用 ATD 相比。拟议的研究具有创新性，因为它们将增强 了解 PDEF 在抑制前列腺癌转移中的作用并帮助我们评估其有效性 PDEF/Twist-1 在早期检测可能患有侵袭性前列腺癌的患者中具有增强作用 转移潜力。我们的研究的影响将在于开发一种新的方法来区分 前列腺癌的侵袭性和转移性表型来自惰性疾病，特别是 使 AA 男性受益，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