Cyclooxygenase Modulators of Immune Function in Breast Cancer

乳腺癌免疫功能的环氧合酶调节剂

• 批准号: 8008627
• 负责人: Amy M. Fulton
• 金额: $ 4.62万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8008627
• 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

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)酶在上皮性癌中通常过度表达，并与 在乳腺癌和其他恶性肿瘤中预后很差。流行病学研究表明，长期使用 COX抑制剂与原发乳腺癌、结肠癌、肺癌和其他癌症的风险较低有关。我们的长期计划 目标是开发预防或治疗转移性乳腺癌的疗法。我们已经雇佣了临床前研究人员 和临床模型，以确定影响肿瘤转移的因素。我们的研究表明，COX-2 活性有助于乳腺癌的侵袭性行为，环氧合酶-2抑制剂控制肿瘤生长和 通过免疫依赖机制进行转移。初步研究支持这样的假设：考克斯 抑制物改变肿瘤细胞的内在属性，改变刺激和抑制配体的平衡，从而 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 自然杀伤分子-配体调节的功能意义。COX-2产物PGE2介导细胞 通过四个EP受体发出信号进行反应。我们的研究表明了一种抑制乳房的新方法 靶向选择性EP受体的肿瘤转移。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受体通路。第三个目标将定义角色 局限性乳腺癌中肿瘤和宿主细胞表达EP受体的研究使用一大系列的井- 已知长期存活的人类乳腺肿瘤的特征，第四个目标将决定EP 受体或NK配体的表达与人类乳腺癌的行为有关。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 一些EP受体的存在预示着更糟糕的结果。乳腺疾病治疗的最新进展 癌症极大地改善了患有激素依赖型疾病的女性的前景。更少的治疗 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 有吸引力的替代现有疗法和拟议的研究可能会确定一个战略，将促进 先天和获得性手臂的抗肿瘤免疫反应。