Cyclooxygenase Modulators of Immune Function in Breast Cancer

描述(申请人提供)：环氧合酶-2(COX-2)酶通常在上皮性癌中过度表达，并与乳腺癌和其他恶性肿瘤的不良预后有关。流行病学研究表明，长期使用COX抑制剂与患乳腺癌、结肠癌、肺癌和其他癌症的风险较低有关。我们的长期目标是开发预防或治疗转移性乳腺癌的疗法。我们使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，COX-2抑制剂通过免疫依赖机制控制肿瘤的生长和转移。初步研究支持这样的假设，即COX抑制剂改变了肿瘤细胞的内在属性，改变了刺激和抑制配体之间的平衡，这些配体与免疫效应细胞上的受体结合。这些调节使肿瘤靶点对免疫细胞介导的裂解更加敏感。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通过四种EP受体传递信号，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。第三个目标将确定肿瘤和宿主细胞表达的EP受体在局限性乳腺癌中的作用。使用一大系列特征良好的人类乳腺肿瘤，这些肿瘤的长期存活率已知，第四个目标将确定EP受体或NK配体的表达是否与人类乳腺癌的行为有关。这些研究将检验一种假设，即NK激活配体的表达与较好的预后相关，但某些EP受体的存在预示着较差的结果。乳腺癌治疗的最新进展极大地改善了患有激素依赖型疾病的女性的前景。激素非依赖性和晚期疾病的治疗选择较少。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策略，既可以增强抗肿瘤免疫反应的先天和适应性臂，也可以增强抗肿瘤免疫反应的适应性臂。

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.