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）一直被认为是一种很有希望的癌症化学预防剂。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，认为使用硒来预防癌症没有希望。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进行人体疗效验证，基于细胞培养的研究也不支持。相比之下，我们和其他人的许多临床前研究表明，通过摄入其他形式的硒，特别是甲基硒酸（MSeA）和硒-甲基硒半胱氨酸（MSeC），可以抑制前列腺和其他器官部位癌症的发生，这些硒被认为是体内活性抗癌甲基硒醇池的前体。我们最近使用蛋白质组学方法的数据质疑甲基硒醇范式的有效性，并提出了MSeA与MSeC的独特潜在分子靶点，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衰老途径来抑制肿瘤性前列腺病变的生长，预示着通过诱导体内早期病变细胞的不可逆终末阻滞来预防新的范式。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、抑制因子/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。我们提出三个具体目标来验证这一假设：1。对比MSeA/C与（缺乏）SeMet在前列腺特异性Pten-KO小鼠体内对上皮腺癌发生的预防作用，并在Pten和p53双KO小鼠中严格评估p53-p21衰老途径对其疗效的贡献。2. 对比SeMet对化学诱导的雄激素促进的大鼠前列腺癌的体内MSeA/C和缺乏MSeA/C的预防作用，并确定p53-p21衰老激活是否参与其中。3. 从MSeA和MSeC的Aims 1和2以及p53-p21-senescene通路的研究中，鉴定前列腺和前列腺癌中的蛋白质组学特征和分子靶点，并验证鉴定的关键靶点。该研究结果有望为MSeA/C提供可靠的体内疗效数据，这些数据来自多个临床前前列腺癌模型，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）。在多个模型中的积极效果增加了人类应用程序的可翻译性。该结果可能有助于重振和推进硒-前列腺癌化学预防研究领域，重新定义和改变活性硒形态、细胞过程和分子靶点的机制范式。