Validation of Biomarkers to Distinguish Aggressive from Indolent Prostate Cancer

验证区分侵袭性前列腺癌和惰性前列腺癌的生物标志物

基本信息

批准号：
8489433
负责人：
GEORGE WILDING
金额：
$ 20.89万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8489433
关键词：
Adverse effects Androgen Receptor Androgens Anguish Anxiety Apoptosis Benign Benign Prostatic Hypertrophy Biological Markers Biopsy Blood Cancer Etiology Cancer Patient Carcinogens Cell Proliferation Cells Cessation of life Clinic Clinical Complex Data Diagnosis Enzymes Gene Expression Genetic Transcription Genomics Growth Factor Hormones Human Hydrogen Peroxide Indolent Institution LNCaP Laboratories Lead Left Life Malignant Neoplasms Malignant neoplasm of prostate Mass Spectrum Analysis Metabolic Metastatic Prostate Cancer Methods Outcome Oxidative Stress PSA level PSA screening Pathway interactions Patients Play Polyamines Production Prognostic Marker Prostate Prostatectomy Prostatic Prostatic Diseases Prostatic Intraepithelial Neoplasias Proteomics Publications Publishing Radiation therapy Radical Prostatectomy Reactive Oxygen Species Recurrence Refractory Relative (related person)Reporting Resected Resistance Rest Role Sampling Seminal fluid Specificity Spermidine Spermine Tissue Microarray Tissues Transferase Transferase Gene Translations Up-Regulation Urine Validation Virulent autocrine cancer cell cancer diagnosis clinical decision-making feeding follow-up high risk men novel outcome forecast oxidation prevent prostate cancer cell protein expression public health relevance serum PSA transcription factor tumor progression volunteer

项目摘要

DESCRIPTION (provided by applicant): Advanced hormone refractory metastatic prostate cancer (PCa) is the second leading cause of cancer deaths among US men. Persistent increase in serum PSA level has less than 30% specificity for PCa diagnosis leading to overtreatment and unnecessary anxieties and anguish. A widespread application of PSA screening is leading to the diagnosis of an increasing number of low grade and small PCas each year. Left untreated, some of these PCas may progress and become lethal. Many of them, however, may remain indolent for the rest of the patients' life. There is no approved biomarker that can distinguish often lethal PCas from the indolent ones. Natural carcinogens such as reactive oxygen species (ROS) are produced in large excess in a majority of PCa tissues. There is strong evidence that ROS play a key role in the progression of androgen- dependent PCa (ADPCa) to more virulent castrate-resistant PCa (CRPCa). Several publications have demonstrated that one of the ROS (H2O2) plays a central role in expressing certain growth and transcription factors that sustain androgen-dependent PCa cell proliferation in the absence of androgen. Until recently, a mechanism of androgen-induced ROS production remained largely unknown. In the last 5 years, we have established that an increase in the enzymatic activity of spermidine/spermine acetyl transferase (SSAT) is primarily responsible for the cellular ROS production in ADPCa cells. SSAT is the first and a regulatory enzyme in the pathway that converts spermidine and spermine that are produced in large amount in the prostate to their corresponding acetyl derivatives. Oxidation of acetyl-spermidine (ac-spd) and acetyl-spermine (ac-spm) is a major contributor of the androgen-induced ROS production in polyamine-rich PCa cells. Induction of SSAT can be observed in prostate biopsies or in the surgically resected prostate tissues from PCa patients. Prostate SSAT activity may also be observed in all patients from its metabolic products ac-spd and ac-spm in the seminal fluid, blood and urine using mass spectrometry. Here, we propose to validate our hypothesis that an increased SSAT expression in prostate tissues and an elevation of SSAT metabolites ac-spd and/or ac-spd in the seminal fluid, blood or urine could be a reliable indicator to identify patients with poor prognosis. Our Specific Aims are: 1) To quantitate SSAT gene and protein expression in several resected prostate tissue microarrays (TMA) consisting of normal prostate, benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), localized low grade PCa, high grade PCa and metastatic PCa available at our Institution along with patient biopsy and prostatectomy samples obtained from the Marshfield Clinic, Marshfield, WI. 2) To quantitate acetyl-spermine and acetyl-spermidine levels in collected seminal fluids, blood and urine samples from PCa patients and normal volunteers. 3) To correlate the data collected in Aims #1 and #2 with patient outcome to validate the SSAT expression and the ac-spd and/or the ac-spm level in the semen, blood or urine samples of PCa patients. The threshold values of these biomarkers should help identify patients with high risk of progression.

描述（由申请人提供）：晚期激素难治性转移性前列腺癌（PCA）是美国男性癌症死亡的第二大原因。血清PSA水平的持续增加对于PCA诊断的特异性小于30％，导致过度治疗和不必要的焦虑和痛苦。 PSA筛查的广泛应用导致每年诊断出越来越多的低级PCA和小型PCA。未经治疗，其中一些PCA可能会进展并变得致命。但是，其中许多人可能在其余患者的寿命中保持懒惰。没有批准的生物标志物可以将经常致命的PCA与懒惰的PCA区分开。在大多数PCA组织中，天然致癌物（例如活性氧（ROS））大量产生。有强有力的证据表明，ROS在依赖性PCA（ADPCA）对更具毒性的耐Castrate PCA（CRPCA）的进展中起关键作用。几个出版物表明，其中一个ROS（H2O2）在表达某些生长和转录因子方面起着核心作用，这些因素和转录因子在没有雄激素的情况下维持依赖雄激素的PCA细胞增殖。直到最近，雄激素诱导的ROS产生的机制在很大程度上尚不清楚。在过去的5年中，我们确定精子/精子乙酰转移酶（SSAT）的酶活性增加主要负责ADPCA细胞中的细胞ROS产生。 SSAT是途径中的第一个和一种调节酶，它转化了在前列腺中大量产生的精子和精子，以其相应的乙酰衍生物产生。乙酰基 - 胸膜（AC-SPD）和乙酰乳腺（AC-SPM）的氧化是雄激素诱导的多胺PCA细胞中雄激素诱导的ROS产生的主要因素。可以在前列腺活检或PCA患者的外科手术切除的前列腺组织中观察到SSAT的诱导。使用质谱法中的所有代谢产物AC-SPD和AC-SPM的患者中，也可以观察到前列腺SSAT活性。在这里，我们建议验证我们的假设，即前列腺组织中SSAT的表达增加以及SSAT代谢物AC-SPD的升高和/或AC-SPD在精液液，血液或尿液中可能是可靠的指标，可以鉴定预后不良的患者。我们的具体目的是：1）在几个切除的前列腺组织微阵列（TMA）中定量SSAT基因和蛋白质表达，由正常前列腺，前列腺良性前列腺增生（BPH）组成，前列腺上皮内肿瘤（PIN），局部较低级PCA，高级PCA，高级PCA的proce sampe，proca，高级PCA的proca，proca，高级PCA，proca，高级PCA，均具有较高的pca，并具有较高的pca属性。威斯康星州马什菲尔德的马什菲尔德诊所。 2）在PCA患者和正常志愿者中收集的乙酰乳房和乙酰 - 胸膜水平定量。 3）将目标＃1和＃2中收集的数据与患者结局相关联，以验证SSAT表达和AC-SPD和/或PCA患者精液，血液或尿液样本中的AC-SPM水平。这些生物标志物的阈值值应有助于确定具有高进展风险的患者。