COX-2 and PPARgamma: Targets for BRCA Prevention

描述（由申请人提供）：环氧化酶-2 （COX-2）和过氧化物酶体增殖激活受体- γ (PPARgamma)已成为预防乳腺癌的有希望的候选者。我们的研究和其他研究表明，COX-2诱导和PPARgamma失活发生在乳腺癌中，它们直接或通过对一系列增殖和凋亡相关基因的协同作用促进癌症诱导。初步研究表明，同时靶向COX-2和PPARgamma对乳腺癌的抑制作用优于单独靶向两种分子。我们假设同时靶向COX-2和PPARgamma可能协同抑制乳腺癌变的发展，这将比单独靶向每个分子更有效。此外，COX-2抑制剂和/或ppargamma激动剂诱导常见的促凋亡信号通路，作为介导其癌症化学预防作用的机制。为了验证我们的假设，我们将评估ppargamma配体N-（9-氟酰-甲基羰基）- l-亮氨酸（F-L-Leu）和COX-2抑制剂塞来昔布在雌性Sprague Dawley大鼠（一种成熟的乳腺癌动物模型）中预防N-甲基- N-亚硝基脲（MNU）诱导的乳腺癌的新组合方案的疗效。为了阐明COX-2抑制剂和pparγ配体预防乳腺癌的机制，我们将（在正常组织和不同癌症阶段）研究塞来昔布和F-L-Leu（单独或联合使用）对介导乳腺内固有凋亡信号的关键基因/蛋白质的影响。我们计划完成以下具体目标：目的1：分别确定F-L-Leu和塞来昔布对大鼠乳腺癌的预防作用。目的2：确定试验药物组合对大鼠乳腺癌的协同预防效果。目的3：通过评估试验药物对启动乳腺细胞凋亡信号通路的影响，阐明试验药物预防乳腺癌变的机制。这是首次详细评估同时靶向COX-2和PPARgamma作为乳腺癌预防新策略的临床前工作。这项研究的结果可以：1)提供COX-2抑制剂和ppargamma配体之间的协同相互作用的见解，2)阐明这些药物介导癌症预防的机制，3)为它们在预防人类乳腺癌方面的最终临床应用奠定基础。

DESCRIPTION (provided by applicant): Cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor-gamma (PPARgamma) have emerged as promising candidates for the prevention of breast cancer. Our studies and those of others suggest that COX-2 induction and inactivation of PPARgamma occur in breast cancer and that they contribute to cancer induction either directly or via their coordinate action on an array of proliferation- and apoptosis-related genes. Preliminary studies indicate that targeting both COX-2 and PPARgamma can inhibit mammary cancer to an extent superior to that produced by targeting each molecule alone. We hypothesize that simultaneous targeting of COX-2 and PPARgamma may act synergistically to inhibit the development of mammary gland carcinogenesis, which would be more effective than targeting each molecule alone. Furthermore, COX-2 inhibitors and/or PPARgamma-agonists induce common pro-apoptotic signaling pathways as a mechanism that mediates their cancer chemopreventive action. To test our hypothesis, we will assess the efficacy of a novel combinational regimen of the PPARgamma-ligand N-(9- fluorenyl-methyloxycarbonyl)-L-Leucine (F-L-Leu) and the COX-2 inhibitor celecoxib on the prevention of N-methyI- N-nitrosourea (MNU)-induced mammary cancer in female Sprague Dawley rats, a well-established animal model of breast cancer. To elucidate the mechanisms by which COX-2 inhibitors and PPARgamma-ligands prevent mammary cancer, the effects of celecoxib and F-L-Leu (separately and in combination) will be examined (both in normal tissues and at different cancer stages) on genes/proteins that play a critical role in mediating intrinsic apoptotic signaling in the mammary gland. We plan to accomplish the following specific aims: Aim 1: determine the dose-response effects of F-L-Leu and celecoxib, separately, on the prevention of rat mammary cancer. Aim 2: determine the synergistic preventive efficacy of a combination of the test drugs on rat mammary cancer. Aim 3: elucidate the mechanisms by which the test drugs prevent mammary gland carcinogenesis by evaluating their effects on molecular pathways that initiate apoptotic signaling in the mammary gland. This is the first detailed preclinical effort to evaluate targeting COX-2 and PPARgamma simultaneously as a novel strategy for breast cancer prevention. The results of this study can: i) provide insight into the synergistic interaction between COX-2 inhibitors and PPARgamma-ligands, ii) elucidate the mechanisms by which these agents mediate cancer prevention and iii) establish the basis for their eventual clinical use in the prevention of human breast cancer.