Role of chemokine receptor in disparities associated with prostate cancer progres

趋化因子受体在前列腺癌进展相关差异中的作用

• 批准号: 9340094
• 负责人: Shailesh Singh
• 金额: $ 9.58万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2019-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340094
• 关键词: Affect; African American; American; Antibodies; Apoptosis; Behavior; Benign; Biological Markers; CCL25 gene; Castration; Cell Line; Cell Survival; Cells; Cessation of life; Clinical; Data; Development; Disease; Disease Outcome; Doxycycline; Drug resistance; Epithelium; European; Event; Exhibits; GPR-9-6 receptor; Goals; Homing; Immunohistochemistry; In Vitro; Incidence; Injectable; Intervention; Knock-out; LNCaP; Laboratories; Ligands; Luciferases; Malignant neoplasm of prostate; Mediating; Molecular; Molecular Target; Monitor; Mus; Neoplasm Metastasis; Outcome; Pathologic; Pathway interactions; Patients; Pharmacology; Phenotype; Phosphorylation; Play; Pre-Clinical Model; Prognostic Marker; Prostate; Regimen; Resistance; Role; Sampling; Serum; Signal Transduction; Signaling Molecule; Small Interfering RNA; Testing; Therapeutic; Tissues; Treatment Efficacy; base; bone; cancer health disparity; castration resistant prostate cancer; cell growth; cell motility; chemokine; chemokine receptor; chemotherapy; clinical efficacy; clinically relevant; design; docetaxel; health disparity; improved; in vitro Assay; in vivo; in vivo imaging; inhibitor/antagonist; innovation; insight; men; migration; mouse model; neoplastic cell; neutralizing antibody; novel; organ growth; outcome forecast; overexpression; pre-clinical; prostate cancer cell; prostate cancer cell line; public health relevance; racial disparity; response; standard care; standard of care; therapeutic target; therapy outcome; therapy resistant; trafficking; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): African-American (AA) men have higher incidence of prostate cancer (PCa) than European American (EA). Furthermore, PCa in AA men is characterized by poor prognosis and dismal therapeutic outcomes. However, the mechanism/s associated with this health disparity remain unclear. Thus, identification of molecular mechanisms underlying such disparity is greatly desired in order to develop effective therapeutic and management approaches. It is becoming well appreciated that the chemokine-ligand axis is crucially involved in tumor cell trafficking and the development of organ-specific metastases, which is the major cause of PCa associated deaths. Our laboratory is the first to show that CC chemokine receptor 9 (CCR9) is selectively overexpressed in prostate cancers with negligible expression in normal prostate epithelia. Our exciting preliminary data show significantly higher expression of CCR9 in AA PCa cell lines and clinical samples compared to cell lines and clinical samples derived from EA. Furthermore, serum CCL25, which is natural ligand for CCR9 was higher in AA and PCa cell lines from AA (MDA-PCa-2b) and showed higher invasive and migratory potential as well as less response to chemotherapeutics in vitro compared to EA cell lines (C4-2b). Based upon these encouraging data, we hypothesize that CCR9-CCL25 axis underlies the poor prognosis and therapeutic outcome in AA men with PCa. To test our hypothesis, we propose to investigate the CCR9- CCL25 mediated mechanism associated with (i) aggressive cell phenotype in AA samples, (ii) homing and tumor growth in bone and the potential role of this chemokine-receptor axis in improving chemotherapeutic efficacy of clinical regimens in AA patients. We further aim to establish CCR9 as a biomarker for PCa progression and aggressive disease. To accomplish our aims, we have generated CCR9 anti-body against CCR9 and CCL25, which will be used to block this axis during in vitro assays to determine its role in migration, invasion, survival and chemoresistance; determining its potential role in metastasis as well as determining therapeutic efficacy of Docetaxel in vivo using AA and EA cell lines. In addition, siRNA duplexes or specific pharmacological inhibitors against CCR9 driven signaling molecules will be used to dissect the CCR9 mediated mechanism involved in migration, invasion, survival and chemoresistance. We are optimistic that the successful completion of these studies will define the role of this newly identified chemokine in PCa health disparity. Furthermore, it will enable the design and development of rational therapies directed against the CCR9-CCL25 to reduce/eliminate disparity in therapeutic outcomes.

描述（由申请人提供）：非裔美国人（AA）男性的前列腺癌发病率（PCA）高于欧美（EA）。此外，AA男士的PCA的特征是预后不良和治疗结果令人沮丧。但是，与这种健康差异相关的机制尚不清楚。因此，为了开发有效的治疗方法和管理方法，非常需要鉴定这种差异的分子机制。人们非常理解的是，趋化因子 - 配体轴与肿瘤细胞的运输至关重要，并且是器官特异性转移的发展，器官特异性转移是PCA相关死亡的主要原因。我们的实验室是第一个表明CC趋化因子受体9（CCR9）在正常前列腺上皮中可忽略不计的前列腺癌中有选择性表达的。我们令人兴奋的初步数据显示，与来自EA的细胞系和临床样品相比，AA PCA细胞系和临床样品中CCR9的表达明显更高。此外，与EA细胞系相比，AA（MDA-PCA-2B）的CCR9天然配体的血清CCL25在AA（MDA-PCA-2B）的AA和PCA细胞系中较高，并且与EA细胞系相比，对体外化学治疗剂的反应较小，对化学治疗剂的反应较小（C4-2B）。基于这些令人鼓舞的数据，我们假设CCR9-CCL25轴是AA患有PCA的男性的预后和治疗结果不佳的基础。为了检验我们的假设，我们建议研究AA样品中与（i）与（i）侵袭性细胞表型相关的CCR9-CCL25介导的机制，（ii）骨骼中的归因和肿瘤生长以及该趋化因子受体轴在改善AA患者临床方案的化学治疗功效方面的潜在作用。我们进一步旨在将CCR9建立为PCA进展和攻击性疾病的生物标志物。为了实现我们的目标，我们已经对CCR9和CCL25产生了CCR9抗体，该抗体将在体外测定期间用于阻断该轴，以确定其在迁移，入侵，生存和化学上的作用。确定其在转移中的潜在作用，并确定使用AA和EA细胞系在体内的治疗功效。此外，针对CCR9驱动的信号分子的siRNA双链体或特定的药理抑制剂将用于剖析涉及迁移，入侵，存活和化学抗性的CCR9介导的机制。我们乐观的是，这些研究的成功完成将定义这种新鉴定的趋化因子在PCA健康差异中的作用。此外，它将能够针对CCR9-CCL25的理性疗法的设计和开发，以减少/消除治疗结果的差异。