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：
8829786
负责人：
JUNXUAN LU
金额：
$ 31.91万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
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 2015-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8829786
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 Oncogene Proteins Oncogenic Oral Organ Outcome Paper Pathway interactions Patients Pharmaceutical Preparations Placebo Control Pre-Clinical Model Prevention Preventive Prostate Prostate carcinoma Prostatic 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 Taxane Compound 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 pre-clinical preclinical efficacy preclinical study prevent prostate cancer model prostate cancer prevention prostate carcinogenesis 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）被认为作为癌症化学预防剂具有广阔的前景。然而，最近在北美结束的使用硒代蛋氨酸 (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：使用硒来预防癌症没有希望。然而，我们不敢苟同这样的主流观点。从这些执行良好的临床研究中得到的一个代价高昂的教训是，无论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 进行人体功效验证，基于细胞培养的研究也不支持选择 SeMet。相比之下，我们小组和其他人的许多临床前研究表明，通过超营养摄入其他形式的硒，特别是甲基硒酸（MSeA）和硒-甲基硒代半胱氨酸（MSeC）可以抑制前列腺癌和其他器官部位癌症的发生。），体内活性抗癌甲基硒醇池的假定前体。我们最近使用蛋白质组学方法获得的数据对甲基硒醇范式的有效性提出了质疑，并提出了 MSeA 与 MSeC 的独特潜在分子靶标，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，MSeA 超级激活 p53-p21-衰老途径，可抑制临床前小鼠模型中的肿瘤性前列腺病变生长，预示着通过诱导不可逆转的新预防范例体内早期病变细胞的最终停滞。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-细胞凋亡；抑制/癌蛋白平衡）来预防临床前啮齿动物模型中的前列腺癌发生。我们建议通过 3 个具体目标来检验这一假设： 1. 对比 MSeA/C 与（缺乏 SeMet）对前列腺特异性 Pten-KO 小鼠上皮腺癌发生的体内预防功效，并严格评估使用 Pten 和 p53 双 KO 小鼠研究 p53-p21 衰老途径的功效。 2. 比较 MSeA/C 与 SeMet 缺乏体内预防功效对大鼠体内化学诱导、雄激素促进的前列腺癌发生的作用，并确定是否涉及 p53-p21 衰老激活。 3. 除了 p53-p21-senescene 通路外，还通过 MSeA 和 MSeC 的目标 1 和 2 研究来鉴定前列腺和前列腺癌中的蛋白质组特征和分子靶点，并验证已鉴定的关键靶点。预计结果将为代表不同人类 PCa 病因和不同哺乳动物物种（小鼠和大鼠）的多种前列腺癌临床前模型的 MSeA/C 提供可靠的体内疗效数据。多种模型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复兴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。