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)被认为是一种很有前途的癌症化学预防药物。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，认为使用硒预防癌症是没有希望的。然而，我们不同意这种主流观点。从这些执行良好的临床研究中得到的一个昂贵的教训是，无论在决定进行这些试验时存在的临床前疗效数据如何，都不支持选择赛美特进行人类疗效验证，基于细胞培养的研究也不支持。相比之下，我们团队和其他人的许多临床前研究表明，其他形式的硒的超营养摄入可以抑制前列腺癌和其他器官部位的癌症的发生，特别是甲基硒酸(MSEA)和硒-甲基硒半胱氨酸(MSSEC)，它们是体内活性抗癌甲基硒醇池的假定前体。我们最近的数据用蛋白质组学的方法质疑了甲基硒醇范例的有效性，并提出了MSEA与MSSEC的独特的潜在分子靶点，几乎没有重叠。我们在器官特异性Pten基因敲除(KO)驱动的前列腺癌发生中的最新数据表明，MSEA通过过度激活P53-p21-衰老通路来抑制临床前小鼠模型中的肿瘤前列腺病变的生长，预示着通过在体内诱导早期病变细胞的不可逆转的末端停滞来实现一种新的预防模式。我们的中心假设是，MSEA/C可以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；抑制者/癌蛋白平衡)来预防临床前啮齿动物模型的前列腺癌的发生。1.比较MSEA/C和(缺乏)SeMet对前列腺特异性Pten-KO小鼠上皮腺癌形成的预防作用，并用Pten和P53双KO小鼠评价P53-p21衰老通路对其疗效的影响。2.比较MSEA/C和Semet对化学诱导的雄激素诱导的大鼠前列腺癌的体内预防作用，并确定是否参与了P53-p21的衰老激活。3.鉴定前列腺癌和前列腺癌的蛋白质组学特征和分子靶点，从MSEA和MSEC的AIMS 1和2以及P53-p21-senescene途径的研究中鉴定并验证已识别的关键靶点。这些结果有望为MSEA/C提供可靠的体内疗效数据，这些模型代表了不同的人类前列腺癌病因和不同的哺乳动物物种(小鼠和大鼠)的前列腺癌的多种临床前模型。多种模型的正效应增加了人类应用的可译性。这一结果可能有助于复兴和推进前列腺癌化学预防研究领域，重新定义和改变活性硒形式的机制范式(S)、细胞过程和分子靶点。