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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）：尽管前列腺癌（PCa）治疗的临床药物最近有所增加，但激素难治性转移性疾病占前列腺癌骨骼转移死亡的绝大多数（~90%），特别是骨骼转移。目前大多数用于前列腺癌的化疗方案，包括多西他赛，基本上是非选择性地靶向快速分裂的细胞群，因此呈现衰弱毒性。其他主要限制是由于雄激素不依赖性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，选择性地提出了低增殖，