IGF::OT::IGF PROSTATE CANCER PREVENTION BY ASPIRIN AND/OR OTHER NSAIDS TORFP 2016-E03HHSN2612015000381PERIOD OF PERFORMANCE: 07/07/2016 - 03/06/2019

前列腺癌(PC)是美国最常见的癌症，也是男性癌症死亡的第二大原因。两个主要的第三阶段PC化学预防试验未能产生支持食品和药物管理局(FDA)批准各自的预防药物的结果。在非前列腺癌预防试验中，基于前景看好的次级终点而选择的硒和维生素E，在硒和维生素E癌症预防试验(SELECT)中都没有显示出降低PC的益处，尽管维生素E可以观察到PC的增加。前列腺癌预防试验(PCPT)显示，服用非那雄胺可以降低PC的风险，但确实发生的癌症往往级别更高，这阻碍了该试剂被批准为降低风险的适应症。因此，需要一种有效但无毒的化学预防干预措施来降低PC风险。 阿司匹林已在多项观察性研究和临床试验中被证明与降低一些癌症的风险有关，特别是胃肠道恶性肿瘤。阿司匹林的这一特点，加上其相对无毒和有益的心血管作用，表明阿司匹林是一种有前途的化学预防药物。尽管对PC的益处不如对胃肠道癌症，但几项荟萃分析显示，使用阿司匹林可使PC发病或死亡的风险降低10%。同样，随机试验表明死亡风险降低。然而，虽然阿司匹林预防结肠癌和乳腺癌已经在临床前环境中进行了广泛的研究，但还没有针对PC进行类似的研究。阿司匹林和其他非类固醇抗炎药(NSAIDs)的预防作用机制很复杂。然而，它们的抗炎活性，包括抑制环氧合酶1和2(COX-1，2)，导致几种前列腺素(PG)和血栓素A的减少，已成为潜在的抗癌机制的核心。这可能特别适用于涉及炎症的PC。 已经提出了解释阿司匹林和其他非类固醇抗炎药抗癌活性的其他机制。其中包括增强免疫系统，这表明这些药物具有潜在的免疫治疗效果。例如，有证据表明，非类固醇抗炎药通过阻止PGE2诱导的单核细胞成熟为免疫抑制的髓系来源抑制细胞(MDSCs)来限制癌症的发生。NSAID活动的这一额外领域表明，将阿司匹林等药物与免疫干预相结合在预防领域是有希望的。然而，在将阿司匹林/非甾体抗炎药与免疫策略相结合之前，需要单独对前者进行适当的临床前研究。先前的经验表明，临床前疗效研究是人类后续临床试验结果的关键预测因素。一个鲜明的例子是在动物研究中预测的选择试验中观察到的负面预防结果。 一个有希望的PC动物模型的例子是TMPRSS2-ERG融合小鼠。PC中反复发生的染色体重排涉及TMPRSS2基因5‘非翻译区和Ets家族基因的并列，Ets家族基因由ERG和Ets等癌基因转录因子组成。TMPRSS2基因是一种前列腺特异性的、雄激素反应的跨膜丝氨酸蛋白酶基因，而ETS和ERG基因编码的转录因子导致细胞增殖。在约50%的局限性前列腺癌中观察到TMPRSS2未翻译的5‘外显子与ERG或ETS“癌基因”的融合，通常与癌基因(“ERG”)的过度表达有关。当融合时，TMPRSS2在雄激素刺激下上调导致“ERG”基因成分的激活，从而促进细胞增殖。在基因工程TMPRSS2-ERG融合小鼠模型中，TMPRSS2-ERG融合结构受控于ARR2-PROBASURE启动子，该启动子已被用于前列腺癌和前列腺上皮内瘤变的模型。然而，TMPRSS2-ERG融合本身并不能诱导侵袭性前列腺癌的前兆--前列腺上皮内肿瘤(PIN)。相反，它需要伴随着PI3激酶通路的激活，例如，通过PTEN的失活。在TMPRSS2-ERG融合小鼠模型中测试阿司匹林的支持来自一项基于小群体的PC病例对照研究，在该研究中，在融合阳性病例中观察到使用阿司匹林的相对风险显著降低，但在融合阴性病例中观察到使用阿司匹林的相对风险显著降低。

Prostate cancer (PC) is the most common cancer and the second leading cause of cancer death in men in the United States. Two major phase III PC chemoprevention trials failed to yield results supportive of Food and Drug Administration (FDA) approval of the respective agents for prevention. Selenium and vitamin E, chosen based on promising secondary endpoints in non-PC prevention trials, both failed to show a benefit in PC reduction in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), although an increase in PC was observed with vitamin E. The Prostate Cancer Prevention Trial (PCPT) demonstrated a decrease in PC risk with finasteride, but cancers that did occur tended to be of higher grade, discouraging approval of the agent for a risk-reducing indication. Thus, a need exists for an effective but non-toxic chemopreventive intervention for PC risk reduction. Aspirin has been shown in multiple observational studies and clinical trials to be associated with reduction in risk of a number of cancers, particularly malignancies of the gastrointestinal tract. This feature, together with its relative non-toxicity and beneficial cardiovascular effects, suggests aspirin as a promising chemopreventive agent. Although the benefits are less for PC than for GI cancers, several meta-analyses have shown a 10% reduction in risk of developing or dying from PC in association with aspirin use. Similarly, randomized trials have demonstrated a decrease in risk of death. Yet, while prevention of colon and mammary cancers with aspirin has been studied extensively in the preclinical setting, no similar studies have been carried out for PC. The mechanisms underlying the preventive activity of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are complex. However, their anti-inflammatory activity, including inhibition of cyclo-oxygenases 1 and 2 (COX-1, 2), resulting in reduction of several prostaglandins (PGs) as well as thromboxane A, have held center stage as potential anti-cancer mechanisms. This may be particularly applicable to PC, which involves inflammation. Additional mechanisms to explain the anti-cancer activity of aspirin and other NSAIDs have been proposed. Among these is enhancement of the immune system, suggesting a potential immunological therapeutic effect by these agents. As one example, evidence suggests that NSAIDs limit carcinogenesis by preventing PGE2-induced maturation of monocytes into immunosuppressive myeloid derived suppressor cells (MDSCs). This additional domain of NSAID activity suggests that combining agents such as aspirin with immunological interventions holds promise in the area of prevention. Prior to combining aspirin/NSAIDs with immune strategies, however, appropriate preclinical studies of the former alone are required. Prior experience has shown that preclinical efficacy studies are critical predictors of outcomes in follow-up clinical trials in humans. A stark example is the negative preventive outcomes observed in the SELECT trial which were predicted by animal studies. A promising example of an animal model of PC is the TMPRSS2-ERG fusion mouse. A recurrent chromosomal rearrangement in PC involves juxtaposition of the 5’ untranslated region of the TMPRSS2 gene and ETS family genes, which consist of oncogenic transcription factors such as ERG and ETS. The TMPRSS2 gene is a prostate-specific, androgen-responsive, transmembrane serine protease gene, whereas the ETS and ERG genes encode transcription factors that lead to cell proliferation. Fusions of the TMPRSS2 untranslated 5’ exons to the ERG or ETS “cancer genes” are observed in about 50% of localized prostate cancers and are generally associated with overexpression of the oncogene (“ERG”) component. When fused, upregulation of TMPRSS2 in response to androgen stimulation leads to activation of the “ERG” gene component and hence to cell proliferation. In the genetically engineered TMPRSS2-ERG fusion mouse model, the TMPRSS2-ERG fusion construct is under the control of the ARR2-Probasin promoter, which has been used in previous models of prostate cancer and prostate intraepithelial neoplasia. However, the TMPRSS2-ERG fusion alone does not induce prostate intraepithelial neoplasia (PIN), a precursor to invasive PC. Rather, it requires concomitant activation of the PI3 kinase pathway, as for example, via inactivation of PTEN. Support for the testing of aspirin in a TMPRSS2-ERG fusion mouse model comes from a small population-based case-control study of PC in which a significant reduction in relative risk with aspirin use was observed for fusion-positive cases, but not fusion-negative cases.