Development of Metabolomic and Molecular Probes for Prostate Cancer Assessment

描述（由申请人提供）：前列腺癌（PCa）PSA检测的发展导致早期潜伏性PCa的诊断增加，这些早期潜伏性PCa在患者的一生中可能不会变得具有临床意义。不幸的是，缺乏识别这些病例的临床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PCa生长速率和侵袭性的工具，以促进在不同护理阶段将相对惰性的肿瘤与更具威胁性的肿瘤进行精确和准确的区分，从而有利于患者的健康并降低整体护理成本。根据公布的数据和我们的初步结果，本项目将检验这样一种假设，即PCa的生长和攻击潜力可以通过用完整组织磁共振波谱（MRS）测量精胺和柠檬酸盐水平以及用实时定量（rt-q）定量精胺合成/降解和柠檬酸锌复合物途径中mRNA的表达水平来评估对激光捕获显微切割（LCM）获得的不同病理组分进行PCR。具体而言，我们将根据定量病理学测量PCa生长速率与代谢组学谱、精胺和柠檬酸盐浓度的相关性，以及与精胺合成/降解途径中的酶和锌摄取蛋白hZIP 1的mRNA表达水平的相关性，所述mRNA表达水平用于从临床证实的良性前列腺增生（BPH）、前列腺增生（PAH）、前列腺增生症（BPH）、前列腺增生症（PAH）、前列腺增生症（BPH）和前列腺增生症（BPH）患者中用LCM分离的不同病理组分。前列腺上皮内肿瘤（PIN）和不同等级的前列腺癌（PCa），所有这些都具有可靠的PSA速度（Vpsa），该PSA速度是根据多个PSA结果随时间计算的。我们将回顾性地测量PCa侵袭性与这些测量的生物学参数的相关性，这些生物学参数用于年龄、Gleason评分（GS）、病理分期和化疗匹配的PCa患者，在前列腺切除术后有或没有癌症生化复发（BCR）。这些研究的成功将使我们能够建立一个PCa的生化诊断系统，该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。这些结果将帮助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，并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。

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.