Breast cancer prevention with COX-2 and EGFR inhibitors

使用 COX-2 和 EGFR 抑制剂预防乳腺癌

• 批准号: 6915115
• 负责人: Susan Patricia Lanza-Jacoby
• 金额: $ 7.85万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6915115
• 关键词: antineoplastics; biomarker; breast neoplasms; carcinogenesis; chemoprevention; combination cancer therapy; combination chemotherapy; epidermal growth factor; female; inhibitor /antagonist; laboratory mouse; metastasis; nonhuman therapy evaluation; nonsteroidal antiinflammatory agent; oxidoreductase inhibitor; prostaglandin endoperoxide synthase; protein tyrosine kinase; protooncogene; receptor binding; women' s health

DESCRIPTION (provided by applicant): Breast cancer that does not respond to estrogen (estrogen receptor negative) comprises 30% of invasive breast cancers. These tumors are more aggressive, tend to metastasize, and have a poor prognosis. Cyclooxygenase (COX)-2 and the epidermal growth factor receptor (EGFR) may be potential targets in breast cancer prevention and treatment. COX 2 is overexpressed in many types of human tumors including breast. The COX-2 inhibitors have been shown to reduce the incidence of colon and mammary tumors in rodents and inhibit the growth of established mammary tumors. Although their mechanism of action is not clear, these drugs have been shown to inhibit the COX enzyme, reduce prostaglandin synthesis, and suppress angiogenesis, which is essential for tumor growth. EGFR is overexpressed in both estrogen receptor positive and estrogen receptor negative human breast cancers and is also associated with a poor prognosis. ZD1839 (Iressa) is a potent antitumor agent that targets EGFR tyrosine kinase and has been shown to reduce proliferation and angiogenesis. The purpose of this study is to test whether ZD1839 alone will prevent mammary tumors in a mouse model of estrogen receptor negative breast cancer that overexpresses HER-2/neu; and whether ZD 1839 in combination with the COX-2 inhibitor celecoxib will be more effective than either agent alone. The specific aims are: 1. To demonstrate that ZD1839 will reduce incidence, multiplicity, and metastasis of mammary tumors in HER-2/neu mice. 2. To assess whether ZD 1839 will interact with celecoxib, i.e., whether the combination treatment will achieve a reduction in the incidence of mammary tumors in HER-2/neu mice above and beyond what would be expected by the sum of the individual main effects of the two agents. 3. To identify changes in biomarkers associated with the protective effects of the combination ofZD1839 plus celecoxib against mouse mammary tumorigenesis. Specifically, we will identify biomarkers that: (a) are affected by the different treatments; and (b) are associated with the presence/absence of tumors. This study will provide evidence to support the use of the combined treatment of Iressa plus celecoxib for prevention of breast cancer. These findings may also help define biomarker genes associated with the protective effects of the treatments, which may ultimately be used to track response to treatment.

描述（由申请人提供）： 对雌激素不反应的乳腺癌（雌激素受体阴性）占浸润性乳腺癌的30％。这些肿瘤更具侵略性，倾向于转移，预后较差。环氧酶（COX）-2和表皮生长因子受体（EGFR）可能是预防乳腺癌和治疗中的潜在靶标。 Cox 2在包括乳房在内的许多人类肿瘤中过表达。已显示COX-2抑制剂可减少啮齿动物中结肠和乳腺肿瘤的发生率并抑制已建立的乳腺肿瘤的生长。尽管它们的作用机理尚不清楚，但这些药物已被证明可以抑制COX酶，减少前列腺素的合成并抑制血管生成，这对于肿瘤生长至关重要。 EGFR在雌激素受体阳性和雌激素受体负面的人乳腺癌中都过表达，并且预后不良。 ZD1839（IRESSA）是一种靶向EGFR酪氨酸激酶的有效抗肿瘤剂，已被证明可以减少增殖和血管生成。这项研究的目的是测试单独的ZD1839是否会预防雌激素受体阴性乳腺癌的小鼠模型中乳腺肿瘤过表达HER-2/NEU； ZD 1839与COX-2抑制剂Celecoxib是否比单独使用任何一种药物更有效。具体目的是：1。证明ZD1839将减少HER-2/NEU小鼠乳腺肿瘤的发病率，多重性和转移。 2。为了评估ZD 1839是否会与Celecoxib相互作用，即组合处理是否会减少HER-2/NEU小鼠在HER-2/NEU小鼠中的发生率，超出了两种药物的个体主要影响的总和。 3。确定与ZD1839组合的保护作用相关的生物标志物的变化，以及塞来昔布对小鼠乳腺肿瘤发生的变化。具体来说，我们将确定：（a）受不同治疗的影响； （b）与肿瘤的存在/不存在有关。这项研究将提供证据，以支持使用IRESSA和CELECOXIB的联合治疗来预防乳腺癌。这些发现还可能有助于定义与治疗的保护作用相关的生物标志物基因，这些基因最终可用于跟踪治疗的反应。