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：
7347611
负责人：
Amy M. Fulton
金额：
$ 27.83万
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 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7347611
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 Genus Cola Goals Histocompatibility Antigens Class I Hormonal Hormones Human Immune Immune response In Vitro Lesion Ligands Localized 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 Patients Population Property Prostaglandin E Receptor Prostaglandin-Endoperoxide Synthase Protein Overexpression Risk Role Series Signal Transduction Solid Stream T-Lymphocyte T-Lymphocyte and Natural Killer Cell Testing Therapeutic Tumor Angiogenesis Upper arm Woman base cyclooxygenase 1 cyclooxygenase 2 follow-up human WFDC2 protein immune function immunogenic improved malignant breast neoplasm neoplastic cell novel novel strategies outcome forecast pre-clinical prevent protein expression receptor response selective expression tumor tumor growth tumorigenic

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：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不良预后相关。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。我们采用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 活性有助于乳腺癌的侵袭性行为，并且 COX-2 抑制剂通过免疫依赖性机制控制肿瘤生长和转移。初步研究支持这样的假设：COX 抑制剂改变肿瘤细胞的内在特性，改变与免疫效应细胞上的受体结合的刺激和抑制配体的平衡。这些调节使肿瘤靶标对免疫细胞介导的裂解更加敏感。目标 1 将使用药理学和遗传学方法确定自然杀伤配体调节的功能意义。 COX-2 产物 PGE2 通过四个 EP 受体发出信号来介导细胞反应。我们的研究表明了一种通过靶向选择性 EP 受体来抑制乳腺癌转移的新方法。第二个目标将继续确定调节转移行为和 NK 活性的相关 EP 受体途径。第三个目标将定义肿瘤和宿主细胞表达的 EP 受体在局部乳腺癌中的作用。第四个目标将使用大量特征明确的人类乳腺肿瘤（已知其长期存活率）来确定 EP 受体或 NK 配体表达是否与人类乳腺癌的行为相关。这些研究将检验这样的假设：NK 激活配体的表达与更好的预后相关，但某些 EP 受体的存在表明预后更差。乳腺癌治疗的最新进展极大地改善了患有激素依赖性疾病的女性的前景。对于激素非依赖性疾病和晚期疾病，可用的治疗选择较少。基于免疫的疗法是现有疗法的有吸引力的替代方案，拟议的研究可能会确定一种可以增强抗肿瘤免疫反应的先天性和适应性的策略。