Gender Selectivity to Colon Cancer Chemoprevention by NSAIDS

描述(申请人提供)：结直肠癌(CRC)是美国人癌症死亡的第二大原因。通过对腺瘤性息肉进行适当的筛查和切除，降低结直肠癌的风险是非常有希望的。然而，只有约50%的高危人群(50岁)接受了任何形式的筛查，许多人接受了敏感度不佳的测试。这突显了开发替代癌症预防策略的必要性，例如化学预防。在众多所谓的药物中，非类固醇抗炎药(NSAIDs)已经可靠地显示出积极的结果。事实上，流行病学、实验和临床试验明确指出了非类固醇抗炎药预防结直肠癌的益处。然而，疗效相对较小(风险降低30%-50%)，需要十多年才能显示出显著的好处。此外，非类固醇类药物的使用已被证明与严重的副作用有关，包括溃疡、胃肠道出血、出血性中风等，因此警告说，在预防结直肠癌方面，风险可能超过阿司匹林和非类固醇类药物的好处。因此，为了改进风险-效益分析，关键是要有选择地针对能够对非类固醇抗炎药的化学预防效果做出有效反应的受试者，同时排除最不可能受益的人群。可以想象，有反应的患者可以以较低的有效剂量进行靶向，以避免相关的毒性。性别是结直肠癌的重要危险因素，女性往往有生物差异(近端病变的患病率较高，DNA错配修复缺陷肿瘤等)。雌激素是公认的预防结直肠癌的化学预防药物。此外，我们的研究小组报告说，女性改变了对遗传和环境因素的易感性。流行病学数据有一些研究表明，NSAIDs的化学预防反应有所改善，尽管文献中有不一致的报告。因此，女性是否对NSAID的化学预防更敏感的问题尚未解决，可能是NSAID的类型、剂量等发挥作用。我们最近进行了一项化学预防试验，使用非甾体抗炎药塞来昔布在一种得到充分验证的肠道肿瘤发生模型MIN小鼠中。我们注意到，在这个模型中，女性对塞来昔布的化学预防作用更敏感。化学预防反应被发现具有区域性倾向，在近端肠道有较强的疗效。此外，塞来昔布治疗的雌性小鼠粘膜雌激素受体-2(ER2)水平更高。我们假设，在结直肠癌中，非甾体抗炎药在女性中表现出更高的化学预防效果，这可能是雌激素受体ER2表达调节的次要作用。公共卫生相关性：结直肠癌是美国的主要公共卫生问题之一，一生中被诊断为这种癌症的风险约为6%。这种癌症通常发展缓慢(10-15年)，通过从正常结肠粘膜到腺瘤再到癌的多种遗传和表型转变。这一旷日持久的进展为内窥镜筛查和摘除腺瘤性息肉等干预提供了充足的时间。这很有希望，但只有大约一半的高危人群(50岁)接受了任何形式的有效筛查。这突显了开发替代癌症预防策略的必要性，例如化学预防。大量研究表明，非类固醇抗炎药(NSAIDs)对结直肠癌具有化学预防作用。然而，总体疗效相对温和(风险降低30%-50%)，需要十多年才能显示出显著的好处。此外，非甾体抗炎药的使用已被证明与严重的副作用有关，包括溃疡、胃肠道出血、出血性中风等，因此在用于预防结直肠癌的平均风险使用方面造成了一些不确定性。因此，为了改进风险-收益分析，选择能够有效地对非类固醇抗炎药物(NSAIDs)的化学预防效果做出反应的受试者是至关重要的。最近有研究表明，患有结直肠癌的女性对饮食营养素或药物的反应可能与男性不同，因为她们可能有不同的病理、风险因素和激素状况。流行病学研究表明，妇女对NSAIDs的化学预防反应有所改善，尽管文献中有不一致的报告。因此，女性是否对NSAID的化学预防更敏感的问题尚未解决，可能是NSAID的类型、剂量等发挥作用。拟议的研究将探讨雌激素在非类固醇抗炎药的性别选择性化学预防效果中的作用。这些发现将对结肠癌化学预防的保健建议产生重要影响，这些建议必须认识到非甾体抗炎药的这种性别选择性功效，以最大限度地发挥非甾体抗炎药的成本效益潜力。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer deaths among Americans. With proper screening and removal of adenomatous polyps, CRC risk reduction has been very promising. However, only ~50% of the at-risk population (age >50) receives any sort of screening and many undergo tests with suboptimal sensitivity. This underscores the need for developing alternate cancer prevention strategies such as chemoprevention. Of the myriad of purported agents, nonsteroidal anti-inflammatory drugs (NSAIDS) have reliably shown a positive outcome. Indeed, epidemiological, experimental and clinical trials unequivocally point to the CRC preventive benefits of NSAIDS. However, the efficacy is relatively modest (30-50% risk reduction) and requires more than a decade to show significant benefits. In addition, the use of NSAIDS has been shown linked to severe side-effects including ulcers, GI bleeding, hemorrhagic strokes etc, thereby cautioning that the risks may outweigh the benefits of aspirin and NSAIDS in preventing CRC for average risk use. To improve the risk-benefit analysis, it is therefore critical to selectively target subjects that can efficiently respond to chemopreventive efficacy of NSAIDS and at the same time leave out the population least likely to benefit. It is conceivable that responsive patients could be targeted with lower efficacious doses to avoid associated toxicity. Gender is an important risk factor for CRC with women frequently having biological differences (higher prevalence of proximal lesions, DNA mismatch repair deficient tumors etc). Estrogen is a well-accepted chemopreventive agent against CRC. Moreover, our group has reported that women have altered susceptibility to both genetic and environmental CRC risk factors. The epidemiological data has some studies suggesting an improved chemopreventive response to NSAIDS although there are discordant reports in the literature. Thus, the issue of whether women are more sensitive to NSAID chemoprevention is unresolved with possibility that NSAID type, dose etc may play a role. We recently conducted a chemoprevention trial using the NSAID celecoxib in a well-validated model of intestinal tumorigenesis, the MIN mouse. We noted that in this model, females were more responsive to the chemopreventive effects of celecoxib. The chemopreventive response was found to have regional propensity with stronger efficacy in the proximal intestine. Furthermore, celecoxib treated female mice had higher levels of mucosal estrogen receptor-2 (ER2) levels. We hypothesize that in colorectal cancer, NSAIDS present an increased chemopreventive efficacy in females which may be secondary to modulation of estrogen receptor ER2 expression. PUBLIC HEALTH RELEVANCE: Colorectal cancer is one of the major public health issues in US with life time risk of being diagnosed with this cancer is about 6%. This cancer usually develops slowly (10- 15 years) through multiple genetic and phenotypic transitions from normal colonic mucosa to adenoma and then to carcinoma. This protracted progression provides ample time for interventions such as endoscopic screening and removing adenomatous polyps. This has been promising but only about half of the at-risk population (age >50) receive any sort of effective screening. This underscores the need for developing alternate cancer prevention strategies such as chemoprevention. Number of studies shows that nonsteroidal anti-inflammatory drugs (NSAIDS) exert chemopreventive benefits against CRC. However, the overall efficacy is relatively modest (30-50% risk reduction) and requires more than a decade to show significant benefits. In addition, the use of NSAIDS has been shown to be linked to severe side-effects including ulcers, GI bleeding, hemorrhagic strokes etc, thereby causing some uncertainty in its use for preventing CRC for average risk use. To improve the risk-benefit analysis, it is therefore critical to selectively target subjects that can efficiently respond to chemopreventive efficacy of nonsteroidal anti-inflammatory drugs (NSAIDS). It has recently been shown that women with CRC may respond to dietary nutrients or pharmacological agents differently than men as they may have differing pathologies, risk factors and hormone status. The epidemiological studies suggest an improved chemopreventive response in women to NSAIDS although there are discordant reports in the literature. Thus, the issue of whether women are more sensitive to NSAID chemoprevention is unresolved with possibility that NSAIDS type, dose etc may play a role. The proposed studies will address the role of estrogen in gender selective chemopreventive efficacy of NSAIDS. These findings will have an important bearing on the healthcare recommendations for colon cancer chemoprevention which have to be cognizant of this gender selective efficacy for maximum cost-benefit potential of NSAIDS.