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

基本信息

项目摘要

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食品和药物给药的结果(FDA)批准相应的预防药物。基于非PC预防试验中的承诺次要终点选择的硒和维生素E未能显示出PC减少的硒和维生素E预防癌症预防试验(SELECT)的好处,尽管使用维生素E. PC的增加。用于降低风险的指示。这是对有效但无毒的化学预防干预措施的需求,以降低PC风险。 阿司匹林已在多项观察性研究和临床试验中显示,与许多癌症的风险降低有关,尤其是胃肠道的恶性肿瘤。该特征及其相对无毒和有益的心血管效应表明阿司匹林作为承诺的化学预防剂。尽管对PC的好处少于GI癌,但几个荟萃分析显示,与阿司匹林使用相关的PC出现或死亡的风险降低了10%。同样,随机试验表明死亡风险降低。然而,尽管在临床前的环境中已经对患有阿司匹林的结肠癌和乳腺癌进行了预防,但未对PC进行类似的研究。阿司匹林和其他非甾体类抗炎药(NSAIDS)的预防活性的基础机制是复杂的。然而,它们的抗炎活性,包括抑制环氧酶1和2(Cox-1,2),导致几种前列腺素(PGS)以及血栓烷A的降低以及血栓烷A具有潜在的抗癌机制的中心阶段。这可能特别适用于涉及注射的PC。 已经提出了解释阿司匹林和其他NSAID的抗癌活性的其他机制。其中包括增强免疫系统,表明这些药物具有潜在的免疫治疗作用。一个例子,证据表明,NSAIDS通过防止PGE2诱导的单核细胞成熟到免疫抑制髓样型抑制细胞(MDSC)来限制癌变。 NSAID活动的额外领域表明,将阿司匹林与免疫学干预措施相结合的预防领域有望。但是,在将阿司匹林/NSAID与免疫学策略相结合之前,需要对前者进行适当的临床前研究。先前的经验表明,临床前效率研究是人类随访临床试验中结果的关键预测指标。一个鲜明的例子是通过动物研究预测的选定试验中观察到的负面预防结果。 PC动物模型的一个有希望的例子是TMPRSS2-erg融合小鼠。 PC中的复发染色体重排涉及将TMPRSS2基因和ETS家族基因的5'非翻译区并置,这些区域由ERG和ETS等致癌转录因子组成。 TMPRSS2基因是一种前列腺特异性,雄激素反应性,跨膜丝氨酸蛋白酶基因,而ET和ERG基因编码导致细胞增殖的转录因子。在约50%的局部前列腺癌中观察到TMPRSS2未翻译的5'外显子与ETS或ETS“癌基因”的融合,通常与过度表达ONCOGENE(“ ERG”)成分有关。当融合时,TMPRSS2响应雄激素刺激的上调会导致“ ERG”基因成分的激活,从而激活细胞增殖。在基因设计的TMPRSS2-GERT融合小鼠模型中,TMPRSS2-EGR融合构建体在ARR2-蛋白酶启动子的控制下,该构建体已用于先前的前列腺癌和前列腺内上皮内肿瘤的模型。但是,单独的TMPRSS2-GER融合不会诱导前列腺内肿瘤(PIN),这是侵入性PC的前体。相反,它需要同时激活PI3激酶途径,例如,通过PTEN失活。在TMPRSSS2-ERG融合小鼠模型中对阿司匹林进行测试的支持来自PC的基于人群的小病例对照研究,其中观察到融合阳性病例的相对风险显着降低,但没有观察到融合阳性病例,但没有观察到融合融合的病例。

项目成果

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CHINTHALAPALLY RAO其他文献

CHINTHALAPALLY RAO的其他文献

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{{ truncateString('CHINTHALAPALLY RAO', 18)}}的其他基金

Base Title: PREVENT Preclinical Drug Development Program: Preclinical Efficacy and Intermediate Endpoint BiomarkersTask Order Title: Colorectal Cancer (CRC) Prevention by TPST-1495 in PIRC rat mod
基本标题:预防临床前药物开发计划:临床前功效和中间终点生物标志物任务顺序标题:TPST-1495 在 PIRC 大鼠模型中预防结直肠癌 (CRC)
  • 批准号:
    10927554
  • 财政年份:
    2023
  • 资助金额:
    $ 62.51万
  • 项目类别:
TITLE: BLADDER CANCER CHEMOPREVENTION USING THE ANDROGEN RECEPTOR INHIBITOR APALUTAMIDE
标题:使用雄激素受体抑制剂阿帕鲁胺进行膀胱癌化学预防
  • 批准号:
    10677989
  • 财政年份:
    2022
  • 资助金额:
    $ 62.51万
  • 项目类别:
TASK ORDER TITLE: PREVENTING LUNG ADENOCARCINOMA (LUAD) USING TRAIL INDUCING AGENT, ONC201BASE CONTRACT TITLE: PREVENT PRECLINICAL DRUG DEVELOPMENT
任务单标题:使用踪迹诱导剂预防肺腺癌 (LUAD),ONC201BASE 合同标题:预防临床前药物开发
  • 批准号:
    10705393
  • 财政年份:
    2022
  • 资助金额:
    $ 62.51万
  • 项目类别:
BASE TITLE: PREVENT PRECLINICAL DRUG DEVELOPMENT PROGRAM: PRECLINICAL EFFICACY AND INTERMEDIATE BIOMARKERSTASK ORDER TITLE: PREVENTING FAP-CRC USING
基本标题:预防临床前药物开发计划:临床前疗效和中间生物标志物订单标题:预防 FAP-CRC 使用
  • 批准号:
    10652736
  • 财政年份:
    2022
  • 资助金额:
    $ 62.51万
  • 项目类别:
PREVENT CANCER PRECLINICAL DRUG DEVELOPMENT PROGRAM - A NOVEL MULTI-ANTIGEN VACCINE (TNBCVAX) TO PREVENT TRIPLE NEGATIVE BREAST CANCER
预防癌症临床前药物开发计划 - 预防三阴性乳腺癌的新型多抗原疫苗 (TNBCVAX)
  • 批准号:
    10503245
  • 财政年份:
    2021
  • 资助金额:
    $ 62.51万
  • 项目类别:
PREVENT CANCER PRECLINICAL DRUG DEVELOPMENT PROGRAM - A NOVEL MULTI-ANTIGEN VACCINE (TNBCVAX) TO PREVENT TRIPLE NEGATIVE BREAST CANCER
预防癌症临床前药物开发计划 - 预防三阴性乳腺癌的新型多抗原疫苗 (TNBCVAX)
  • 批准号:
    10678625
  • 财政年份:
    2021
  • 资助金额:
    $ 62.51万
  • 项目类别:
PREVENT EFFICACY POOL: PREVENT CANCER PRECLINICAL DRUG DEVELOPMENT PROGRAM
预防功效池:预防癌症临床前药物开发计划
  • 批准号:
    10411703
  • 财政年份:
    2021
  • 资助金额:
    $ 62.51万
  • 项目类别:
TASK ORDER TITLE: PREVENTING COLORECTAL CANCER USING TRAIL-INDUCING ONC201 ALONE OR IN COMBINATION WITH NSAID
任务单标题:单独使用 TRAIL 诱导 ONC201 或与 NSAID 联合使用预防结直肠癌
  • 批准号:
    10269144
  • 财政年份:
    2020
  • 资助金额:
    $ 62.51万
  • 项目类别:
CHEMOPREVENTION WITH AEROSOLIZED LET-7 MICRORNA IN MOUSE MODELS OF NON-SMALL CELL LUNG CANCER (ADENOCARCINOMA AND SQUAMOUS CELL CARCINOMA)
在非小细胞肺癌(腺癌和鳞状细胞癌)小鼠模型中使用雾化的 Let-7 微小RNA进行化学预防
  • 批准号:
    10020543
  • 财政年份:
    2019
  • 资助金额:
    $ 62.51万
  • 项目类别:
IGF::OT::IGF PREVENT EFFICACY: OPTIMIZATION OF GEM MODELS FOR HIGH-RISK COHORTS OF HUMAN PANCREATIC CYSTADENOMAS, IPMNS, AND PANINS PROGRESSION TO PDAC.
IGF::OT::IGF 预防功效:针对人类胰腺囊腺瘤、IPMNS 和 Panins 进展至 PDAC 高风险群体的 GEM 模型的优化。
  • 批准号:
    9152469
  • 财政年份:
    2015
  • 资助金额:
    $ 62.51万
  • 项目类别:

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