[PQC-3] A Metabolic Pathway Activation Marker for Prostate Cancer Prognosis

[PQC-3] 前列腺癌预后的代谢途径激活标志物

• 批准号: 8687192
• 负责人: Hirak S. Basu
• 金额: $ 75.13万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687192
• 关键词: Adverse effects; Androgens; Apoptosis; Architecture; Basement membrane; Biological Assay; Biological Markers; Biopsy; Blood Circulation; Blood Vessels; Cancer Cell Growth; Cancer Etiology; Cancer Prognosis; Cell model; Cells; Cessation of life; Clinic; Clinical; Clinical Research; Data; Detection; Diagnosis; Diagnostic; Diagnostic Procedure; Disease Outcome; Distant; Endothelium; Engineering; Enzyme Activation; F-Actin; Fluorescence; Genetic Engineering; Gleason Grade for Prostate Cancer; Goals; Growth Factor; Health Care Costs; Hormones; Human; Image; In Vitro; Indolent; Informed Consent; Invaded; Lasers; Lead; Left; Lymphatic vessel; Malignant Neoplasms; Malignant neoplasm of prostate; Matrix Metalloproteinases; Measures; Medical; Metabolic; Metabolic Marker; Metabolic Pathway; Metastatic Prostate Cancer; Metastatic/Recurrent; Methods; Microfluidics; Microscopic; Modification; Multiphoton Fluorescence Microscopy; Neoplasm Metastasis; Organ; Outcome; PC3 cell line; PSA level; PSA screening; Pathway interactions; Patients; Primary Neoplasm; Production; Prognostic Marker; Property; Prostate; Prostatectomy; Publications; Reactive Oxygen Species; Refractory; Relative (related person); Resistance; Rest; Risk; Role; Sampling; Specificity; Spermidine; Spermine; Structural Protein; Suspension substance; Suspensions; System; Testing; Time; Tissue Microarray; Tissue Sample; Tissues; Translations; Visual; autocrine; base; cancer cell; cancer diagnosis; clinical practice; extracellular; feeding; flexibility; in vitro Model; liquid chromatography mass spectroscopy; man; men; mimetics; neoplastic cell; novel; outcome forecast; oxidation; prevent; prognostic; prospective; prostate cancer cell; public health relevance; serum PSA; transcription factor; tumor; tumor microenvironment; tumor progression; validation studies

DESCRIPTION (provided by applicant): For best optimization of therapy, it is helpful to predict the metastatic potential of any localized tumor at the time of diagnosis. This is particularly critcal for prostate cancer (PCa). The widespread application of PSA screening is leading to the detection of an increasing number of low grade and small PCas. Left untreated, some of these PCas may progress and become lethal. Many of them, however, may remain indolent for the rest of the patients' lives. The Gleason scoring (GS) system that is currently practiced to predict the possibility of PCa progression fails to predict the risk, when GS is d7. There is unmet medical need for a method for predicting likelihood of progression of these localized tumors without major changes in the current clinical practice. Hypothesis: There is accumulating evidence that production of reactive oxygen species within PCa cells lead to PCa progression and metastasis. We hypothesize that cancer cells with high cellular ROS will modify the structural protein filamentous actin (F-actin). Such modifications will make the cells flexible enough to squeeze through the gaps surrounding the tumor and invade the blood and lymphatic vessels for circulation. Some of these circulating cells with activated MMPs and modified F-actin will escape the endothelia to metastasize. Our goal is to develop an integrated prognostic test based on growing primary tumor cells obtained from routine prostate biopsies in micro-scale in vitro models of tumor microenvironments and then performing quantitative imaging of FAD fluorescence to determine specific metabolic activities that leads to PCa progression. We will validate this pathway biomarker(s) by correlating the data from patient PCa tissues with disease outcome. Our Specific Aims are: 1) To quantitate the difference between fluorescence properties of wild-type and genetically engineered PCa cell lines with varying levels of activation of the ROS generating pathway in a microfluidic mimetic of the basement membrane and endothelium capable of determining their relative invasive proper- ties, 2) To establish FAD fluorescence intensity and lifetime data collected from multiple prostate TMAs as prognostic markers by correlating the data with patient outcome in a retrospective clinical validation study. The observed changes of FAD fluorescence as an indicator of the enzyme activation will be confirmed by measuring the metabolite levels in the laser captured tissues from the corresponding tissue sections, 3) a) To prepare single cell suspensions of PCa cells from the tissue samples from informed, consented patients and analyze FAD fluorescence and their invasive properties in the microfluidic system as standardized in Aim #1, b) To create a TMA from PCa tissues obtained from the same patients and perform FAD fluorescence analysis as standardized in Aim #2, c) To laser capture cancer tissues from the same TMA sections and estimate the metabolites as standardized in Aim #2 and d) To clinically establish the markers by correlating the data collected in a-c with patient outcome in a prospective clinical study.

描述（由申请人提供）：为了最好地优化治疗，在诊断时预测任何局部肿瘤的转移潜力是有帮助的。这对前列腺癌（PCa）尤其重要。PSA筛查的广泛应用导致越来越多的低级别和小的前列腺癌被检测出来。如果不及时治疗，其中一些PCas可能会发展并变得致命。然而，他们中的许多人可能会在病人的余生中保持惰性。格里森评分（GS）系统，目前用于预测