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

通过阿司匹林和/或其他非甾体抗炎药预防 IGF::OT::IGF 前列腺癌 TORFP 2016-E03HHSN2612015000381执行周期：07/07/2016 - 03/06/2019

• 批准号: 9360885
• 负责人: CHINTHALAPALLY RAO
• 金额: $ 62.51万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-08 至 2018-07-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9360885
• 关键词: 1-Phosphatidylinositol 3-Kinase; 5' Untranslated Regions; Androgens; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Aspirin; Cancer Etiology; Cardiovascular system; Case-Control Studies; Cell Proliferation; Cessation of life; Chemopreventive Agent; Chromosomal Rearrangement; Clinical Trials; Colon Carcinoma; Complex; Contractor; Dinoprostone; ERG gene; ETS Family Gene; Exons; Experimental Designs; Finasteride; Gastrointestinal tract structure; Gene Components; Genetic Engineering; Genetically Engineered Mouse; Human; Immune; Immune response; Immune system; Immunosuppressive Agents; Inflammation; Instruction; Intervention; Intraepithelial Neoplasia; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary Neoplasms; Meta-Analysis; Mus; Myelogenous; Non-Steroidal Anti-Inflammatory Agents; Observational Study; Oncogenes; Oncogenic; Outcome; PTEN gene; Pathway interactions; Peptide Hydrolases; Performance; Pharmaceutical Preparations; Phase; Prevention; Preventive; Prostaglandins; Prostate; Prostate Cancer Prevention Trial; Prostatic Neoplasms; Recurrence; Relative Risks; Risk; Risk Reduction; Second Primary Cancers; Selenium; Selenium and Vitamin E Efficacy Trial; Serine Protease; Staging; Suppressor-Effector T-Lymphocytes; TMPRSS2 gene; Testing; Therapeutic Effect; Thromboxanes; United States; United States Food and Drug Administration; Up-Regulation; Vitamin E; base; cancer chemoprevention; cancer prevention; cancer risk; carcinogenesis; cyclooxygenase 1; efficacy testing; experience; follow-up; immunological intervention; in vivo; men; molecular marker; monocyte; mouse model; outcome prediction; overexpression; population based; pre-clinical; preclinical efficacy; preclinical study; prevent; probasin; promoter; prostate cancer model; prostate cancer prevention; randomized trial; response; transcription factor

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.

前列腺癌 (PC) 是美国男性最常见的癌症，也是男性癌症死亡的第二大原因。两项主要的 III 期 PC 化学预防试验未能产生支持美国食品和药物管理局 (FDA) 批准各自药物的结果。硒和维生素 E 是基于非 PC 预防试验中有希望的次要终点而选择的，但在硒和维生素 E 癌症预防试验 (SELECT) 中，尽管观察到 PC 有所增加，但都未能显示出减少 PC 的益处。与维生素E。前列腺癌预防试验 (PCPT) 表明非那雄胺可降低 PC 风险，但确实发生的癌症往往级别较高，因此阻碍了该药物用于降低风险适应症的批准。因此，需要一种有效但非有效的药物。 -降低 PC 风险的毒性化学预防干预。 多项观察性研究和临床试验表明，阿司匹林可降低多种癌症的风险，尤其是胃肠道恶性肿瘤的风险，这一特性及其相对无毒性和有益的心血管作用表明阿司匹林是一种治疗癌症的药物。尽管阿司匹林对 PC 癌的益处不如对胃肠道癌症的好处，但多项荟萃分析显示，使用阿司匹林可使患 PC 癌或死亡的风险降低 10%。同样，随机试验表明，虽然阿司匹林预防结肠癌和乳腺癌的作用已在临床前进行过研究，但尚未针对 PC 的主要预防作用进行类似的研究。阿司匹林和其他非甾体类抗炎药 (NSAID) 很复杂，但它们的抗炎活性包括抑制环加氧酶 1 和 2 (COX-1, 2)，从而导致几种前列腺素 (PG) 以及血栓素 A 作为潜在的抗癌机制占据了中心地位，这可能特别适用于涉及炎症的 PC。 人们提出了解释阿司匹林和其他非甾体抗炎药抗癌活性的其他机制，其中之一是增强免疫系统，这表明这些药物具有潜在的免疫治疗作用，有证据表明非甾体抗炎药通过预防 PGE2 来限制癌变。诱导单核细胞成熟为免疫抑制性骨髓源性抑制细胞（MDSC）。NSAID 活性的这一额外领域表明，阿司匹林等药物与免疫干预措施的结合在该领域具有广阔的前景。然而，在将阿司匹林/非甾体抗炎药与免疫策略结合之前，需要对前者进行适当的临床前研究，之前的经验表明，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。是在 SELECT 试验中观察到的负面预防结果，这是通过动物研究预测的。 PC 动物模型的一个有前景的例子是 TMPRSS2-ERG 融合小鼠，PC 中的反复染色体重排涉及 TMPRSS2 基因和 ETS 家族基因的 5' 非翻译区的并置，ETS 家族基因由致癌转录因子（如 ERG 和 ERG）组成。 ETS。TMPRSS2 基因是前列腺特异性、雄激素响应性、跨膜丝氨酸蛋白酶基因，而ETS 和 ERG 基因编码导致细胞增殖的转录因子，在大约 50% 的局部前列腺癌中观察到 TMPRSS2 非翻译 5' 外显子与 ERG 或 ETS“癌症基因”的融合，并且通常与癌基因的过度表达有关。当融合时，TMPRSS2 响应雄激素刺激而上调，导致“ERG”基因成分激活，从而导致细胞增殖。工程化 TMPRSS2-ERG 融合小鼠模型中，TMPRSS2-ERG 融合构建体受 ARR2-Probasin 启动子控制，该启动子已用于以前的前列腺癌和前列腺上皮内瘤变模型，但单独的 TMPRSS2-ERG 融合则不能。诱导上皮内瘤变 (PIN)，这是侵袭性 PC 的前兆，相反，它需要同时激活 PI3 前列腺激酶通路。例如，通过灭活 PTEN，在 TMPRSS2-ERG 融合小鼠模型中测试阿司匹林来自一项基于小群体的 PC 病例对照研究，其中观察到融合使用阿司匹林的相对风险显着降低。 -阳性病例，但不包括融合阴性病例。