PREVENTION OF PROSTATE CARCINOGENESIS BY NEXT-GENERATION SELENIUM

下一代硒预防前列腺癌

基本信息

批准号：
9063529
负责人：
JUNXUAN LU
金额：
$ 33.24万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9063529
关键词：
Ablation Acetates Adverse effects Affect American American Association of Cancer Research American Cancer Society Androgens Apoptosis Cancer Etiology Cell Aging Cell Culture Techniques Cell Cycle Arrest Cell physiology Cells Cessation of life Chemicals Chemoprevention Chemopreventive Agent Clinical Research Clinical Trials Cytotoxic agent Data Dietary intake Double-Blind Method Eastern Cooperative Oncology Group Epigenetic Process Epithelial Equilibrium Etiology Event FDA approved Goals Growth Health Hormonal Hormones Human Institution Intake Knock-out Knockout Mice Knowledge Lesion Mainstreaming Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Marshal Mediating Mediator of activation protein Methionine Mind Modeling Molecular Target Mus Mutation North America Nutritional Oncogenes Oncogenic Oral Organ Outcome Paper Pathway interactions Patients Pharmaceutical Preparations Placebo Control Pre-Clinical Model Prevention Preventive Prostate Prostate carcinoma Prostatic Intraepithelial Neoplasias Proteins Proteomics Proto-Oncogene Proteins c-akt Quality of life Radiosurgery Randomized Rattus Recurrence Refractory Disease Regimen Research Research Personnel Resectable Rodent Model Selenium Signal Pathway Signal Transduction Site Solid Southwest Oncology Group Staging TP53 gene Testing Time Transgenic Organisms Translations Uncertainty Validation Vitamin E War Work Yeasts abiraterone abstracting base cancer chemoprevention cancer diagnosis cancer prevention cancer risk carcinogenesis cellular targeting chemotherapy docetaxel in vivo inhibitor/antagonist male meetings men methylselenic acid mouse model neoplastic next generation novel novel therapeutics pre-clinical preclinical efficacy preclinical study prevent prostate cancer model prostate cancer prevention prostate carcinogenesis proteomic signature reverse genetics selenomethylselenocysteine senescence statistics taxane transgenic adenocarcinoma of mouse prostate

项目摘要

DESCRIPTION (provided by applicant): Selenium (Se) has been thought to hold great promise as a cancer chemopreventive agent. However, the negative efficacy outcomes of recently concluded human trials in North America with seleno-methionine (SeMet) for prostate cancer (PCa) prevention (SELECT, HGPIN trials) have caused many to conclude that there is no hope for using Se to prevent cancer. We, however, beg to disagree with such a mainstream opinion. A costly lesson from these well-executed clinical studies is that whatever preclinical efficacy data that existed at the time the decision was made to conduct these trials DID NOT support the choice of SeMet for human efficacy validation, NOR did cell culture-based studies. In contrast, many pre-clinical studies from our group and others have shown inhibition of the genesis of cancers of the prostate and other organ sites by supra-nutritional intake of other Se forms, especially methylseleninic acid (MSeA) and Se- methylselenocysteine (MSeC), the presumed precursors of in vivo active anti-cancer methylselenol pool. Our recent data with a proteomic approach question the validity of the methylselenol paradigm and suggest unique potential molecular targets for MSeA vs. MSeC with little overlap. Our latest data with organ specific Pten- knockout (KO) driven prostate carcinogenesis suggest a super-activation of p53-p21-senescence pathway by MSeA to suppress neoplastic prostatic lesion growth in a preclinical mouse model, heralding in a new prevention paradigm through inducing irreversible terminal arrest of early lesion cells in vivo. Our central hypothesis is that MSeA/C will prevent prostate carcinogenesis in preclinical rodent models each by regulating distinct sets of molecular targets and signaling pathways (e.g., p53-p21-senescence; p53- apoptosis; suppressor/oncoprotein balances). We propose testing this hypothesis with 3 Specific Aims: 1. To contrast the in vivo preventive efficacy of MSeA/C with (the lack thereof) SeMet against epithelial adeno- carcinogenesis in the prostate specific Pten-KO mice and to critically assess the contribution of the p53-p21 senescence pathway to their efficacy using Pten and p53 double KO mice. 2. To contrast the in vivo preventive efficacy of MSeA/C with the lack thereof by SeMet against chemically-induced, androgen-promoted prostate carcinogenesis in rats and to determine whether p53-p21 senescence activation is involved. 3. To identify proteomic signatures and molecular targets in the prostate gland and prostate carcinomas from studies of Aims 1 and 2 of MSeA and MSeC in addition to the p53-p21-senescene pathway and validate identified key targets. The results are expected to provide solid in vivo efficacy data for MSeA/C from multiple preclinical models of prostate carcinogenesis representing diverse human PCa etiologies and different mammalian species (mice and rats). Positive efficacies in multiple models increase the translatability for human application. The results may help to resurrect and advance the field of Se-prostate cancer chemoprevention research, redefining and changing mechanism paradigms of active Se form(s), cellular processes and molecular targets.

描述（由申请人提供）：硒（SE）被认为是癌症化学预防剂的巨大希望。然而，最近在北美结束的人类试验的负效果结果是前列腺癌（PCA）预防（选择，HGPIN试验）的人类试验，这使许多人得出结论，人们没有希望使用SE来预防癌症。但是，我们要不同意这种主流意见。这些执行良好的临床研究的一课是，在决定进行这些试验时存在的任何临床前疗效数据都不支持SEMET选择人类效力验证，也不支持基于细胞培养的研究。 In contrast, many pre-clinical studies from our group and others have shown inhibition of the genesis of cancers of the prostate and other organ sites by supra-nutritional intake of other Se forms, especially methylseleninic acid (MSeA) and Se- methylselenocysteine (MSeC), the presumed precursors of in vivo active anti-cancer methylselenol pool.我们使用蛋白质组学方法的最新数据质疑甲基列醇范式的有效性，并提出了MSEA与MSEC的独特潜在分子靶标，而几乎没有重叠。我们使用器官特异性PTEN敲除（KO）驱动的前列腺癌变的最新数据表明，MSEA通过MSEA对p53-P21季节途径进行了超级激活，以抑制临床前小鼠模型中的肿瘤前列腺病变的增长，这是通过诱导不可逆术语的新预防范式中的预防范式中的预防范围，该模型通过可逆性地捕获了早期的lesion in vivo in vivo。我们的中心假设是，MSEA/C将通过调节不同的分子靶标和信号通路集（例如p53-p21播； p53-凋亡；抑制剂/癌蛋白平衡）来预测各种临床前啮齿动物模型中的前列腺癌发生。我们提出了以3个特定目的进行测试：1。将MSEA/C与（缺乏其缺乏）SEMET与前列腺特异性PTEN-KO小鼠中的上皮腺癌发生相比，并使用P53-P21 Seessence Pation for Ploude resse re Effication和PTEN和PTEN和PTEN和PTEN和PTEN和PTEN和PTEN的贡献。 2。为了将MSEA/C的体内预防效果与SEMET缺乏化学诱导的，雄激素促进的前列腺癌发生，并确定是否涉及p53-P21衰老激活。 3。从对MSEA和MSEC的目标1和2的蛋白质组学特征和前列腺癌中的蛋白质组学特征和分子靶标，除了p53-P21-烯烯途径外，并验证了已识别的关键靶标。预计该结果将提供来自前列腺癌变的多种临床前模型的MSEA/C的固体体内疗效数据，该模型代表了多样化的人PCA病因和不同的哺乳动物（小鼠和大鼠）。多种模型的正效率增加了人类应用的转换性。结果可能有助于复活和推进局部癌症化学预防研究，重新定义和变化的活性SE形式的机理范式，细胞过程和分子靶标。