Development of Metabolomic and Molecular Probes for Prostate Cancer Assessment

用于前列腺癌评估的代谢组学和分子探针的开发

• 批准号: 8205493
• 负责人: Leo L Cheng
• 金额: $ 22.86万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-14 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8205493
• 关键词: Adjuvant Therapy; Age; Aggressive behavior; Benign Prostatic Hypertrophy; Biochemical; Biological; Biological Assay; Biopsy; Cancer Patient; Caring; Cells; Citrates; Clinic; Clinical; Clinical Protocols; Complex; Data; Degradation Pathway; Development; Diagnosis; Diagnostic; Early Diagnosis; Engineering; Enzymes; Evaluation; Gleason Grade for Prostate Cancer; Growth; Human; Hyperplasia; Individual; Indolent; Knowledge; Lead; Life; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Messenger RNA; Metabolic; Metabolism; Methods; Modality; Molecular; Molecular Biology; Molecular Probes; Molecular Profiling; Morphology; Pathological Staging; Pathology; Pathway interactions; Patients; Personal Satisfaction; Polymerase Chain Reaction; Prostate; Prostate Adenocarcinoma; Prostate-Specific Antigen; Prostatectomy; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Proteins; Publishing; Quality of life; Recurrence; Screening for cancer; Screening procedure; Serum; Specimen; Spermine; Staging; Survival Rate; System; Testing; Time; Tissues; Work; Zinc; base; cancer prevention; cancer recurrence; clinically significant; cost; insight; laser capture microdissection; latent prostate cancer; metabolomics; outcome forecast; patient population; preclinical study; success; tool; tumor; uptake

DESCRIPTION (provided by applicant): The development of PSA testing for prostate cancer (PCa) resulted in rising diagnoses of early latent PCa that may not become clinically significant in a patient's lifetime. Unfortunately, a lack of clinical capability to identify these cases often leads to aggressive treatments that unnecessarily reduce the quality of life for this large patient population. Tools that can measure PCa growth rate and aggressiveness are urgently needed to facilitate the precise and accurate differentiation of relatively indolent tumors from more threatening ones at different stages of care to benefit the well-being of the patients and reduce costs of care on the whole. Based on published data and our preliminary results, this project will test the hypothesis that PCa growth and aggression potential may be evaluated through measurement of spermine and citrate levels with intact-tissue magnetic resonance spectroscopy (MRS) and quantification of the expression levels of mRNAs in the spermine synthesis/degradation and zinc-citrate complex pathways with real-time quantitative (rt-q) PCR for different pathological components obtained from laser capture microdissection (LCM). Specifically, we will measure correlations of PCa growth rates with metabolomic profiles, spermine and citrate concentrations according to quantitative pathology, and with expression levels of mRNAs for enzymes in the spermine synthesis/degradation pathways and zinc uptake protein, hZIP1, for different pathological components isolated with LCM from patients of clinically proven benign prostatic hyperplasia (BPH), prostatrophic hyperplasia (PAH), prostatic intraepithelial neoplasm (PIN), and different grades of prostate adenocarcinomas (PCa), all with reliable PSA velocity (Vpsa) calculated from multiple PSA results over time. We will retrospectively measure correlations of PCa aggressiveness with these measured biological parameters for age-, Gleason-score- (GS), pathological-stage-, and adjuvant-therapy-matched PCa patients with and without cancer biochemical recurrence (BCR) after prostatectomies. Success of the studies will enable us to establish a biochemical diagnostic system for PCa that expands the current morphology-based pathology to include information on tumor metabolism and molecular biology. These results will help clinicians assess bioactivity in specific tumors, determine patient prognosis, and select the most appropriate therapy for individual patients and contribute profound understanding of human malignancy and provide new insights into possible new directions for cancer prevention, diagnosis, and treatment. PUBLIC HEALTH RELEVANCE: Annual screening of blood serum prostate specific antigen has resulted in the discovery of a greater number of patients with non-life-threatening indolent prostate tumors, from which the current pathology cannot differentiate lethal ones. Therefore, assessment of prostate cancer aggressiveness is critically needed but currently unavailable in the clinic. In this project, based on our preliminary results, we will test the hypothesis that the alterations in spermine and citrate, and levels of enzyme mRNAs in spermine synthesis/degradation and Zinc-citrate complex pathways correlate with prostate cancer aggressiveness. The significance of the results from this project will increase overall patient survival rates and quality of life, as well as change the paradigm of current prostate cancer practice.

描述（由申请人提供）：前列腺癌PSA检测的发展导致早期潜伏性前列腺癌的诊出率上升，这些前列腺癌在患者的一生中可能没有临床意义。不幸的是，缺乏临床识别这些病例的能力往往导致积极的治疗，不必要地降低了这一庞大患者群体的生活质量。迫切需要能够测量前列腺癌生长速度和侵袭性的工具，以便在不同的护理阶段精确和准确地区分相对惰性的肿瘤和更具威胁性的肿瘤，以造福患者的福祉，并从整体上降低护理成本。根据公布的数据和我们的初步结果，该项目将通过完整组织磁共振波谱（MRS）测量精胺和柠檬酸盐水平，以及实时定量（rt-q） PCR对激光捕获显微解剖（LCM）获得的不同病理成分中精胺合成/降解和锌-柠檬酸盐复合物途径中mrna表达水平的定量，来验证PCa生长和攻击潜力的假设。具体来说,我们将测量相关性的PCa增长率与代谢组学资料、精胺和柠檬酸浓度根据定量病理学和mrna的表达水平精胺合成/酶的降解途径和锌吸收蛋白质,hZIP1,不同病理组件隔离模块从患者的临床证明良性前列腺增生(BPH), prostatrophic增生(PAH)、前列腺上皮内瘤(PIN),以及不同级别的前列腺腺癌（PCa），所有这些都有可靠的PSA速度（Vpsa）， Vpsa是根据多次PSA结果计算的。我们将回顾性测量前列腺癌侵袭性与年龄、gleason评分（GS）、病理分期和辅助治疗匹配的前列腺癌患者（前列腺切除术后有无肿瘤生化复发（BCR））的生物学参数的相关性。这些研究的成功将使我们能够建立一个前列腺癌的生化诊断系统，将目前基于形态学的病理学扩展到包括肿瘤代谢和分子生物学的信息。这些结果将有助于临床医生评估特定肿瘤的生物活性，确定患者预后，并为个体患者选择最合适的治疗方法，有助于对人类恶性肿瘤的深刻理解，并为癌症预防，诊断和治疗的可能新方向提供新的见解。