PREVENTION OF PROSTATE CARCINOGENESIS BY NEXT-GENERATION SELENIUM

下一代硒预防前列腺癌

• 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
• 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

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。然而，最近在北美结束的硒蛋氨酸（SeMet）预防前列腺癌（PCa）的人体试验（SELECT，HGPIN试验）的负面疗效结果使许多人得出结论，使用硒预防癌症没有希望。然而，我们不同意这种主流意见。从这些执行良好的临床研究中得出的一个代价高昂的教训是，无论在决定进行这些试验时存在什么临床前疗效数据，都不支持选择SeMet进行人体疗效验证，NOR进行了基于细胞培养的研究。相比之下，来自我们小组和其他人的许多临床前研究已经显示，通过超营养摄入其他Se形式，特别是甲基硒酸（MSeA）和Se-甲基硒代半胱氨酸（MSeC），体内活性抗癌甲基硒醇库的推定前体，抑制前列腺和其他器官部位的癌症的发生。我们最近的数据与蛋白质组学方法的问题的有效性甲基硒醇范例，并建议独特的潜在分子靶MSeA与MSec几乎没有重叠。我们关于器官特异性Pten-敲除（KO）驱动的前列腺癌发生的最新数据表明，在临床前小鼠模型中，MSeA超激活p53-p21-衰老途径以抑制肿瘤性前列腺病变生长，预示着通过诱导体内早期病变细胞的不可逆终末停滞的新预防范例。 我们的中心假设是，MSeA/C将通过调节不同的分子靶点和信号通路（例如，p53-p21-衰老; p53-凋亡;抑制/癌蛋白平衡）。我们建议用3个具体目标来检验这一假设：1。在前列腺特异性Pten-KO小鼠中对比MSeA/C与SeMet（缺乏）对上皮腺癌发生的体内预防功效，并使用Pten和p53双KO小鼠严格评估p53-p21衰老途径对其功效的贡献。2.对比MSeA/C的体内预防功效与SeMet对化学诱导的雄激素促进的大鼠前列腺癌发生的缺乏，并确定是否涉及p53-p21衰老激活。3.从MSeA和MSeC的目标1和2以及p53-p21-衰老途径的研究中确定前列腺和前列腺癌中的蛋白质组特征和分子靶标，并验证确定的关键靶标。预期这些结果将为来自代表不同人类PCa病因和不同哺乳动物物种（小鼠和大鼠）的前列腺癌发生的多个临床前模型的MSeA/C提供可靠的体内疗效数据。多种型号的积极功效增加了人类应用的可翻译性。这些结果可能有助于恢复和推进硒-前列腺癌化学预防研究领域，重新定义和改变活性硒形式，细胞过程和分子靶点的机制范式。