Characterizing Prostate Cancer By ex vivo MRS Signatures

描述(申请人提供)：血清前列腺特异性抗原检测改善了前列腺癌的早期发现，增加了诊断前列腺癌(PCA)的发病率，并将新检测到的前列腺癌治疗转移到了早期阶段。这些成功也引起了对早期PCa有效管理的争议，主要是：(1)通过组织采样错误在无症状的患者中发现了非常常见的假阴性活检结果，这些患者携带的PCA很小，分布不均；(2)大多数新发现的肿瘤的恶性潜力不确定，活检时的PCA病理相似，但PCA统计数据表明，这些肿瘤将追踪截然不同的疾病路径。提高PCA诊断和预后方法的敏感度/特异度将解决这两个紧迫需求。我们最初的R01研究使用了高分辨率魔角旋转质子磁共振波谱(HRMAS 1HMRS)，我们开发这种技术可以进行完整的组织分析并与病理相关联，从而产生概念验证的PCA代谢标记物。然后，我们发展了PCA代谢组学，并证明了PCA代谢组学提高了PCA检测、诊断和表征的准确性。通过对来自PCa患者的组织学定义的良性前列腺组织的轮廓分析，我们可以通过显示非局部化的PCA代谢场效应或代谢组场的存在来识别PCa的病理分期并预测PCa复发。这些PCA代谢学领域：1)产生组织良性组织中的PCA签名的测量，因此可能通过指示假阴性活检患者存在PCA来减少组织学抽样错误，以及2)有能力预测活检阳性患者的PCA恶性潜能。因此，PCA代谢组学领域可能对PCA临床做出最大贡献，通过区分侵袭性和惰性疾病，并通过支持对惰性肿瘤的主动监测或暗示患者存在侵袭性PCA并需要及时制定辅助治疗的标记物来告知治疗策略。我们最初的R01研究的这些重要结果构成了我们更新应用的基础，其中我们建议：(1)系统地研究位于和超出其病理起源的PCA腺体中的PCA代谢物和代谢组谱的空间分布，以精确地定义PCA代谢组场标记；(2)使用已知临床结果的银行PCA组织样本来测试PCA代谢谱对PCA生长速度、生化复发和治疗反应的预测，以及通过激光捕获显微解剖和实时定量PCR从这些样本中分析与遗传谱相关的不同病理成分；以及(3)通过纵向患者随访，通过预测活检阴性患者的PCA风险和活检阳性患者进入主动监测的适宜性，建立PCA代谢物、代谢组谱和代谢组场作为代谢组学标准的预后能力，以应对当前PCA临床的最终挑战。

DESCRIPTION (provided by applicant): Serum prostate specific antigen testing improved early detection of prostate tumors, increased diagnosed prostate cancer (PCa) incidence, and shifted newly detected PCa treatment to earlier stages. These successes also generated controversies for effective management of earlier-stage PCa, chiefly: (1) the all-too-common false-negative biopsy finding through tissue sampling errors in asymptomatic patients who harbor small, heterogeneously distributed PCa; and (2) the uncertain malignant potential of most newly detected tumors, with PCa pathologies similar at biopsy but which PCa statistics indicate will trace drastically different disease paths. Greater sensitivity/specificity for PCa diagnostic and prognostic approaches would address both these urgent needs. Our original R01 studies used high resolution magic-angle-spinning proton magnetic resonance spectroscopy (HRMAS 1HMRS), which we developed to permit intact tissue analysis and correlation with pathology, in order to produce proof-of-concept PCa metabolic markers. We then developed PCa metabolomics and demonstrated that PCa metabolomic profiles improve accuracy in PCa detection, diagnosis, and characterization. Profile analyses of histologically-defined benign prostate tissue from PCa patients allowed us to identify PCa pathological stage and predict PCa recurrence by showing the existence of delocalized PCa metabolomic field-effects, or metabolomic fields. These PCa metabolomic fields: 1) yield measures of PCa signatures in histo-benign tissue and thus are likely to reduce histological sampling errors by indicating PCa presence for patients with false-negatives biopsies, and 2) have the capacity to predict PCa malignant potential for patients with positive biopsies. Thus PCa metabolomic fields are likely to contribute most significantly to the PCa clinic by distinguishing aggressive from indolent disease and informing treatment strategies through markers that support active surveillance for indolent tumors or suggest that the patient harbors an aggressive PCa and needs timely institution of adjuvant therapies. These significant outcomes from our original R01 studies comprise the basis for our renewal application, in which we propose: (1) to systematically investigate spatial distributions of PCa metabolites and metabolomic profiles localized at and delocalized beyond their pathological origins in PCa glands to precisely define PCa metabolomic field markers; (2) to use banked PCa tissue samples with known clinical outcomes to test PCa metabolomic profile predictions of PCa growth rate and biochemical recurrence and therapy response, as well as to analyze different pathological components associated with genetic profiles from these same samples via laser capture microdissection and real-time quantitative PCR; and (3) to establish, through longitudinal patient follow-up, the prognostic ability of PCa metabolites, metabolomic profiles, and metabolomic fields as metabolomic criteria that answer the ultimate challenges of the current PCa clinic by predicting PCa risk for biopsy-negative patients and the suitability of entering active surveillance for biopsy-positive patients.