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

• 批准号: 8642164
• 负责人: Hirak S. Basu
• 金额: $ 16.13万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8642164
• 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

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 水平持续升高对 PCa 诊断的特异性低于 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别和小型前列腺癌。 如果不及时治疗，其中一些前列腺癌可能会进展并致命。然而，他们中的许多人可能会在患者的余生中保持惰性。目前还没有经过批准的生物标志物可以区分致命性前列腺癌和惰性前列腺癌。大多数 PCa 组织中都会过量产生活性氧 (ROS) 等天然致癌物质。有强有力的证据表明，ROS 在雄激素依赖性前列腺癌 (ADPCa) 发展为毒性更强的去势抵抗性前列腺癌 (CRPCa) 过程中发挥着关键作用。 一些出版物表明，其中一种 ROS (H2O2) 在表达某些生长和转录因子方面发挥着核心作用，这些因子在缺乏雄激素的情况下维持雄激素依赖性 PCa 细胞增殖。 直到最近，雄激素诱导的 ROS 产生的机制仍然很大程度上未知。在过去 5 年中，我们已经确定亚精胺/精胺乙酰转移酶 (SSAT) 酶活性的增加是 ADPCa 细胞中细胞 ROS 产生的主要原因。 SSAT 是将前列腺中大量产生的亚精胺和精胺转化为其相应的乙酰衍生物的途径中的第一个也是调节酶。乙酰亚精胺 (ac-spd) 和乙酰精胺 (ac-spm) 的氧化是富含多胺的 PCa 细胞中雄激素诱导的 ROS 产生的主要贡献者。 SSAT 的诱导可以在前列腺活检或 PCa 患者手术切除的前列腺组织中观察到。还可以使用质谱法从精液、血液和尿液中的代谢产物 ac-spd 和 ac-spm 观察所有患者的前列腺 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 表达增加以及精液、血液或尿液中 SSAT 代谢物 ac-spd 和/或 ac-spd 升高可能是识别预后不良患者的可靠指标。我们的具体目标是： 1) 对我们机构提供的几种切除的前列腺组织微阵列 (TMA) 中的 SSAT 基因和蛋白表达进行定量，其中包括正常前列腺、良性前列腺增生 (BPH)、前列腺上皮内瘤变 (PIN)、局部低级别 PCa、高级别 PCa 和转移性 PCa，以及从患者活检和前列腺切除样本中获得的样本。 马什菲尔德诊所，马什菲尔德，威斯康星州。 2) 定量PCa患者和正常志愿者收集的精液、血液和尿液样本中乙酰精胺和乙酰亚精胺的水平。 3) 将目标 #1 和 #2 中收集的数据与患者结果相关联，以验证 PCa 患者精液、血液或尿液样本中的 SSAT 表达以及 ac-spd 和/或 ac-spm 水平。这些生物标志物的阈值应有助于识别具有高进展风险的患者。