Development of Metabolomic and Molecular Probes for Prostate Cancer Assessment

描述(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断增加，在患者的一生中可能不会变得有临床意义。不幸的是，缺乏识别这些病例的临床能力往往会导致积极的治疗，这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生长速度和侵袭性的工具，以促进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，以造福患者并从整体上降低护理成本。基于已发表的数据和我们的初步结果，本项目将检验这一假设，即可以通过完整组织磁共振波谱(MRS)测量精胺和柠檬酸水平，以及利用实时定量(RT-Q)PCR对激光捕获显微切割(LCM)获得的不同病理成分的精胺合成/降解和锌-柠檬酸复合途径中mRNAs的表达水平进行量化，来评估PCA的生长和攻击潜能。具体地说，我们将测量PCA增长率与代谢组、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吸收蛋白hZIP1的mRNAs表达水平的相关性，这些都是从临床证实的良性前列腺增生症(BPH)、前列腺增生症(PAH)、前列腺上皮内肿瘤(PIN)和不同级别的前列腺癌(PCA)患者的LCM分离出来的，所有这些都具有可靠的PSA速度(Vpsa)。我们将对年龄、Gleason评分(GS)、病理分期和辅助治疗相匹配的有或无前列腺癌术后生化复发(BCR)的PCa患者的这些测量的生物学参数与PCa侵袭性的相关性进行回顾性研究。这些研究的成功将使我们能够建立一个用于PCa的生化诊断系统，将当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，为个别患者选择最合适的治疗方法，并有助于加深对人类恶性肿瘤的理解，为癌症的预防、诊断和治疗提供新的见解。 公共卫生相关性：每年对血清前列腺特异性抗原进行筛查，发现了更多患有非危及生命的惰性前列腺癌的患者，目前的病理学无法将其与致命性前列腺癌区分开来。因此，评估前列腺癌的侵袭性是非常必要的，但目前还不能在临床上获得。在这个项目中，我们将根据我们的初步结果，检验精胺和柠檬酸盐的变化，以及精胺合成/降解和锌-柠檬酸复合体途径中酶mRNAs的水平与前列腺癌侵袭性相关的假设。该项目结果的重要性将提高总体患者存活率和生活质量，并改变当前前列腺癌实践的范式。

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.