Cyclooxygenase Modulators of Immune Function in Breast Cancer

乳腺癌免疫功能的环氧合酶调节剂

基本信息

批准号：
8205136
负责人：
Amy M. Fulton
金额：
$ 1.3万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8205136
关键词：
Apoptosis Behavior Binding Breast Breast Adenocarcinoma Breast Cancer Treatment Cell Line Cell physiology Cells Chronic Clinical Colon Complex Coxibs Cyclooxygenase Inhibitors Cytolysis Development Dinoprostone Disease Effector Cell Enzymes Epidemiologic Studies Epithelial Equilibrium G-Protein-Coupled Receptors Genetic Goals Histocompatibility Antigens Class I Hormonal Hormones Human Immune Immune response In Vitro Lesion Ligands Localized Disease Lung MHC Class I Genes Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Modeling Mus Natural Killer Cells Neoplasm Metastasis Outcome Pathway interactions Population Property Prostaglandin E Receptor Prostaglandin-Endoperoxide Synthase Risk Role Series Signal Transduction Solid Stream T-Lymphocyte T-Lymphocyte and Natural Killer Cell Testing Therapeutic Tumor Angiogenesis Woman advanced disease arm base cyclooxygenase 2 follow-up human WFDC2 protein immune function immunogenic improved malignant breast neoplasm neoplastic cell novel novel strategies outcome forecast overexpression patient population pre-clinical prevent protein expression receptor response selective expression therapy development tumor tumor growth tumorigenic

项目摘要

The cyclooxygenase-2 (COX-2) enzyme is commonly overexpressed in epithelial cancers and is associated with a poor prognosis in breast and other malignancies. Epidemiological studies show that chronic use of COX inhibitors is associated with a lower risk of primary breast, colon, lung and other cancers. Our long term goal is to develop therapies that will prevent or treat metastatic breast cancer. We have employed preclinical and clinical models to define the factors that contribute to tumor metastasis. Our studies show that COX-2 activity contributes to aggressive breast cancer behavior and that COX-2 inhibitors control tumor growth and metastasis by immune-dependent mechanisms. Preliminary studies support the hypothesis that COX inhibitors alter intrinsic properties of tumor cells, altering the balance of stimulating and inhibiting ligands that engage receptors on immune effector cells. These modulations render the tumor target more sensitive to immune cell-mediated lysis. Using pharmacologic and genetic approaches, Aim 1 will determine the functional significance of Natural Killer-ligand modulations. The COX-2 product PGE2 mediates cellular responses by signaling through four EP receptors. Our studies indicate a novel approach to inhibit breast cancer metastasis by targeting selective EP receptors. The second Aim will continue to identify the relevant EP receptor pathways that modulate metastatic behavior and NK activities. The third Aim will define the role of EP receptors expressed by tumor and host cells in localized breast cancer. Using a large series of well- characterized human breast tumors, for which long term survival is known, the fourth Aim will determine if EP receptors or NK ligand expression have relevance to the behavior of human breast cancers. These studies will test the hypothesis that expression of NK-activating ligands is associated with a better prognosis but the presence of some EP receptors indicates a worse outcome. Recent advances in the treatment of breast cancer have greatly improved the outlook for women with hormone-dependent disease. Fewer treatment options are available for hormone-independent and advanced disease. Immune-based therapies are attractive alternatives to existing therapies and the proposed studies may identify a strategy that would boost both innate and adaptive arms of the antitumor immune response.

环氧合酶-2 (COX-2) 酶通常在上皮癌中过度表达，并且与乳腺癌和其他恶性肿瘤的预后较差。流行病学研究表明，长期使用 COX 抑制剂可降低原发性乳腺癌、结肠癌、肺癌和其他癌症的风险。我们的长期目标是开发预防或治疗转移性乳腺癌的疗法。我们已经采用了临床前和临床模型来定义导致肿瘤转移的因素。我们的研究表明COX-2 COX-2 活性有助于侵袭性乳腺癌行为，COX-2 抑制剂可控制肿瘤生长和通过免疫依赖性机制进行转移。初步研究支持 COX 的假设抑制剂改变肿瘤细胞的内在特性，改变刺激和抑制配体的平衡接合免疫效应细胞上的受体。这些调节使肿瘤靶点对免疫细胞介导的裂解。使用药理学和遗传学方法，目标 1 将确定自然杀伤配体调节的功能意义。 COX-2产物PGE2介导细胞通过四个 EP 受体发出信号来响应。我们的研究表明了一种抑制乳腺癌的新方法通过靶向选择性 EP 受体来抑制癌症转移。第二个目标将继续确定相关的调节转移行为和 NK 活性的 EP 受体途径。第三个目标将定义角色局部乳腺癌中肿瘤和宿主细胞表达的 EP 受体。使用大系列的良好描述了人类乳腺肿瘤，其长期存活率已知，第四个目标将确定 EP 是否受体或 NK 配体表达与人类乳腺癌的行为相关。这些研究将检验 NK 激活配体的表达与更好的预后相关的假设，但某些 EP 受体的存在表明结果更差。乳腺治疗的最新进展癌症极大地改善了患有激素依赖性疾病的女性的前景。治疗次数较少对于激素非依赖性疾病和晚期疾病有多种选择。基于免疫的疗法是现有疗法的有吸引力的替代方案和拟议的研究可能会确定一种可以促进治疗的策略抗肿瘤免疫反应的先天性和适应性。