Role of CCL25-CCR9 in Prostate Cancer

CCL25-CCR9 在前列腺癌中的作用

基本信息

批准号：
8638910
负责人：
Shailesh Singh
金额：
$ 35.38万
依托单位：
MOREHOUSE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8638910
关键词：
Ablation Accounting Androgens Antibodies Apoptosis Binding Biological Bone Marrow CCL25 gene Cancer Patient Cell Survival Cells Cessation of life Clinic Clinical Data Development Disease Drug resistance Epithelial Epithelium GPR-9-6 receptor Growth Health Hormones Human Immunohistochemistry Immunoprecipitation In Vitro Injection of therapeutic agent Knock-out Knowledge Laboratories Lead Ligands Light Luciferases Malignant Neoplasms Malignant neoplasm of prostate Matrix Metalloproteinases Mediating Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Molecular Molecular Profiling Molecular Target Monitor Mus Neoplasm Metastasis Organ Outcome PTK2 gene Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Play Population Prostate Prostate Cancer therapy Prostatic Intraepithelial Neoplasias Publishing Refractory Regimen Resistance Role Sampling Series Serum Signal Transduction Signaling Molecule Small Interfering RNA Stromal Cells Testing Tissue Sample Toxic effect Treatment Efficacy base bone cancer cell cell motility chemokine chemokine receptor chemotherapy clinical efficacy deprivation design docetaxel expression vector hormone refractory prostate cancer improved in vitro Assay in vivo in vivo imaging inhibitor/antagonist innovation migration neoplastic cell new therapeutic target novel overexpression paracrine prostate cancer cell response small hairpin RNA standard of care therapeutic target trafficking tumor tumor growth tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Despite recent additions in the clinical armamentarium of drugs for prostate cancer (PCa) therapy, hormone refractory metastatic disease accounts for an overwhelming majority (~90%) of PCa deaths with skeletal metastases, particularly in bones. Most currently-available chemotherapeutic regimens for PCa including docetaxel essentially target rapidly dividing cell populations non-selectively, thus presenting debilitating toxicities. Other major limitations are owing to the emergence of androgen-independence as well as lower proliferative capacity of the metastatic disease. Thus, identification of novel molecular targets that are selectively presented by the less-proliferative, androgen-independent metastatic prostate cancer cells might result in the near-complete elimination of this dreaded disease. It is becoming well appreciated that the chemokine-ligand axis is crucially involved in tumor cell trafficking and the development of organ-specific metastases. Our laboratory is the first to show that CC chemokine receptor 9 (CCR9) is selectively over expressed in prostate cancers with negligible expression in normal prostate epithelia. Our recently published and preliminary data demonstrate that 1) CCR9 is highly expressed by PCa cells and mediates PCa cell migration, invasion and survival in vitro, 2) CCR9 is also highly expressed in clinical prostate cancer tissue samples, 3) CCL25, a natural ligand of CCR9, is expressed in a paracrine manner by PCa clinical sample and also elevated in PCa patient serum, 4) bone marrow stromal cells of tumor-bearing mice significantly produce CCL25, compared to non-tumor bearing ones, 5) inhibition of CCR9-CCL25 axis sensitizes cellular responses to chemotherapy in PCa cells. Based upon these encouraging data, we hypothesize that CCR9-CCL25 axis plays a crucial role in prostate cancer metastasis and is a cancer-selective therapeutic target. Targeting this axis will enable development of new chemotherapeutic strategies as well as improving existing ones by sensitizing prostate cancer cells to currently available regimens. To validate our hypothesis, we propose to determine the role of CCR9-CCL25 axis in (i) inducing prostate cancer cell migration and invasion, (ii) prostate cancer cell survival and apoptosis, (iii) triggering prostate cancer growth and metastases iv) enhancing chemotherapeutic efficacy of clinical regimens. To accomplish our aims, we have generated CCR9 conditional knockout cells that will be used for in vitro assays to determine its role in PCa cell migration, invasion and survival, and determining its potential role in tumor growth, metastasis and therapeutic efficacy of docetaxel. In addition, siRNA duplexes or specific pharmacological inhibitors against CCR9 driven signaling molecules will be used to evaluate the role of CCR9-CCL25 axis in promotion of metastases. We are optimistic that the successful completion of these studies will define the role of this newly identified chemokine in PCa and will go a long way to enhance our understanding of chemokines in mediating disease aggressiveness. Furthermore, it will enable the design and development of rational therapies directed against the CCR9-CCL25 axis for PCa.

描述（由申请人提供）：尽管最近在前列腺癌（PCA）治疗的药物临床武器库中添加了最近的添加，但激素难治性转移性疾病占PCA的绝大多数（〜90％），其中骨骼转移剂，尤其是骨骼转移。 PCA（包括多西他赛）的大多数当前可用的化学治疗方案基本上是非选择性地靶向细胞群体，从而表现出衰弱的毒性。其他主要局限性是由于雄激素独立的出现以及转移性疾病的增殖能力较低。因此，鉴定新的分子靶标，这些靶标有较少的变化，雄激素非依赖性转移性前列腺癌细胞可能会导致这种可怕的疾病几乎完全消除。人们非常理解的是，趋化因子 - 配体轴与肿瘤细胞运输和器官特异性转移的发展至关重要。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具有可忽略的前列腺癌中有选择性表达的。我们最近发表的初步数据表明，1）CCR9由PCA细胞高度表达，并介导PCA细胞迁移，体外的侵袭和生存，2）CCR9在临床前列腺癌组织中也高度表达了CCR9，3）CCL25，CCL25，CCR9的ccr9 ccr9，PCA的PCA，在PCA中表达了PCA，并在PCA中表达了PCA，并在PCA中表达了PCA，并在PCA中表达了PCA，并在PCA中表达了PCA，并在PCA中表达了PCA，并在PCA中表达了PCA。与非肿瘤轴承相比，含有肿瘤小鼠的基质细胞显着产生CCL25，5）抑制CCR9-CCL25轴对PCA细胞中的化学疗法的细胞反应敏感。基于这些令人鼓舞的数据，我们假设CCR9-CCL25轴在前列腺癌转移中起着至关重要的作用，并且是癌症选择性的治疗靶标。针对此轴将能够开发新的化学治疗策略，并通过使前列腺癌细胞对当前可用的方案进行敏感性来改善现有策略。为了验证我们的假设，我们建议确定CCR9-CCL25轴在（i）诱导前列腺癌细胞迁移和侵袭中的作用，（ii）前列腺癌细胞的存活和凋亡，（iii）触发前列腺癌的生长和转移酶IV）增强临床方案的化学治疗性疗效。为了实现我们的目标，我们已经产生了CCR9条件基因敲除细胞，该细胞将用于体外测定，以确定其在PCA细胞迁移，侵袭和存活中的作用，并确定其在多西昔甲梅尔的肿瘤生长，转移和治疗功效中的潜在作用。此外，针对CCR9驱动信号分子的siRNA双链体或特定的药理抑制剂将用于评估CCR9-CCL25轴在促进转移酶中的作用。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中的作用，并将在介导疾病侵略性方面的趋化因子的理解方面大有帮助。此外，它将能够针对PCA的CCR9-CCL25轴的理性疗法的设计和开发。