Cyclooxygenase Modulators of Immune Function in Breast Cancer

描述（由申请人提供）：环氧合酶-2（考克斯-2）通常在上皮癌中过表达，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，长期使用考克斯抑制剂与原发性乳腺癌、结肠癌、肺癌和其他癌症的风险降低有关。我们的长期目标是开发预防或治疗转移性乳腺癌的疗法。我们已经采用临床前和临床模型来定义有助于肿瘤转移的因素。我们的研究表明，考克斯-2活性有助于乳腺癌的侵袭行为，考克斯-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，即考克斯抑制剂改变了肿瘤细胞的内在特性，改变了与免疫效应细胞上的受体接合的刺激和抑制配体的平衡。这些调节使肿瘤靶点对免疫细胞介导的裂解更敏感。使用药理学和遗传学方法，目标1将确定天然杀伤配体调节的功能意义。考克斯-2产物PGE 2通过四种EP受体的信号传导介导细胞反应。我们的研究提示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相关的EP受体途径，调节转移行为和NK活性。第三个目标是确定肿瘤和宿主细胞表达的EP受体在局部乳腺癌中的作用。使用大量的良好表征的人类乳腺肿瘤，其长期存活是已知的，第四个目标将确定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受体的存在表明预后较差的假设。乳腺癌治疗的最新进展极大地改善了患有乳腺癌依赖性疾病的妇女的前景。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，该策略将促进抗肿瘤免疫应答的先天性和适应性臂。

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.