COX-2 and PPARgamma: Targets for BRCA Prevention

描述（由申请人提供）：环氧合酶-2（考克斯-2）和过氧化物酶体增殖物激活受体-γ（PPARgamma）已成为预防乳腺癌的有希望的候选药物。我们和其他人的研究表明，考克斯-2诱导和PPARgamma的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调作用而导致癌症诱导。初步研究表明，同时靶向考克斯-2和PPARgamma可以抑制乳腺癌，其抑制程度上级于单独靶向每种分子所产生的抑制程度。我们假设同时靶向考克斯-2和PPARgamma可能协同作用抑制乳腺癌发生的发展，这将比单独靶向每种分子更有效。此外，考克斯-2抑制剂和/或PPAR γ-激动剂诱导常见的促凋亡信号传导途径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，我们将评估一种新的PPARgamma-配体N-（9-芴基-甲氧羰基）-L-亮氨酸（F-L-Leu）和考克斯-2抑制剂塞来昔布联合方案对预防雌性Sprague道利大鼠（一种成熟的乳腺癌动物模型）中N-甲基-N-亚硝基脲（MNU）诱导的乳腺癌的疗效。为了阐明考克斯-2抑制剂和PPAR γ-配体预防乳腺癌的机制，将检测塞来昔布和F-L-Leu（单独和联合）对在乳腺中介导内在凋亡信号传导中起关键作用的基因/蛋白质的影响（在正常组织和不同癌症阶段）。我们计划完成以下具体目标：目标1：确定F-L-Leu和塞来昔布单独预防大鼠乳腺癌的剂量反应效应。目的2：确定试验药物组合对大鼠乳腺癌的协同预防效力。目标3：通过评价受试药物对启动乳腺细胞凋亡信号传导的分子途径的影响，阐明受试药物预防乳腺癌发生的机制。这是第一个详细的临床前努力，以评估靶向考克斯-2和PPARgamma同时作为一种新的策略，用于预防乳腺癌。本研究的结果可以：i）提供对考克斯-2抑制剂和PPARgamma-配体之间的协同相互作用的洞察，ii）阐明这些药剂介导癌症预防的机制，和iii）建立它们在预防人类乳腺癌中的最终临床应用的基础。

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.