Risk-stratification of Prostate Cancers via Field Carcinogenesis Nanocytology

 描述(申请人提供)：尽管广泛的PSA人群筛查，前列腺癌(PC)仍然是男性肿瘤死亡的第二大原因。最令人头疼的临床问题一直是过度诊断：由于大多数无症状的男性前列腺中都有前列腺癌的病灶，但只有一小部分人会死于这种疾病，广泛的筛查导致了许多危害，因为对疾病的病态治疗可能永远不会在临床上显现出来。因此，主动监视(AS)已成为一种替代策略。然而，缺乏可靠的进展生物标志物对其吸收构成了很大的障碍。迫切需要的是一种新的方法，这种方法能够在常规的AS患者的活检中区分惰性PC和侵略性PC。这个项目的目标就是开发这样一种技术。我们将利用(I)现场致癌之间的协同作用作为生物标志物来源：不仅前列腺肿瘤细胞，而且整个前列腺组织学上更多的正常细胞都带有风险的指纹。这比评估由许多克隆组成的肿瘤本身更好地代表了疾病的自然历史。(2)作为生物标志物的细胞纳米结构：纳米级形态的改变是分子异质性致癌过程的最终公分母。(3)一种新的生物光子学技术--部分波谱(PWS)纳米细胞学，这是目前唯一能够实际测量细胞内纳米结构的技术。一项双盲研究的初步数据显示，在格里森6病患者的组织学正常前列腺活检中，纳米细胞学检测现场癌变的潜力可以作为前列腺癌未来侵袭性的准确预测指标。在这个项目中，我们将测试这样的假设，即显微镜下正常的前列腺组织的PWS纳米细胞学将能够识别侵袭性前列腺癌的风险。我们将开发一种适用于获取PC组织活检切片数据的PWS纳米细胞学系统，识别新的纳米级结构生物标记物以更准确地识别具有临床意义的PC，开发用于处理和分析纳米细胞学活检的可靠方案，并在前瞻性盲法研究中测试预测规则。我们将为遭受PC不成比例痛苦的非裔美国人提供丰富的资金。这种新的方法将在个性化医疗时代与个人电脑管理之间架起一座桥梁。PWS纳米细胞学可以作为分析活检和预测PC后续进展的方案，比目前组织学上可能的更准确和更早地进行。该方法可以与现有的AS方案相结合，而不需要额外的程序，因此对临床实践迅速产生影响。我们的目标是在项目期结束时，该技术将被开发出来，进行临床测试，并为FDA的试验做好准备。

 DESCRIPTION (provided by applicant): Despite the widespread PSA population screening, prostate cancer (PC) still ranks as the second leading cause of neoplastic deaths in men. The most vexing clinical issue has been overdiagnosis: since most asymptomatic men will harbor foci of PC in their prostate, but only a small fraction will die of the disease, widespread screening leads to many harms due to morbid treatment for disease that may never have become clinically apparent. Thus, active surveillance (AS) has emerged as an alternate strategy. However, the lack of reliable biomarkers of progression has presented a large obstacle to its uptake. What is critically needed is a new methodology that would prospectively distinguish indolent from aggressive PC on biopsies routinely obtained from patients on AS. The goal of this project is to develop such a technology. We will take advantage of the synergy among (i) field carcinogenesis as a biomarker source: not only prostate tumor cells but a much larger population of histologically normal cells throughout the prostate bear the fingerprint of risk. This better represents the natural history of the disease then assessing the tumor per se which comprises numerous clones. (ii) Cellular nanoarchitecture as a biomarker: Alterations in nanoscale morphology are the final common denominator for the molecularly heterogeneous carcinogenesis process. (iii) A new biophotonics technology, partial wave spectroscopic (PWS) nanocytology, which is currently the only technology capable of measuring intracellular nanoscale structure in a practical manner. Preliminary data from a double-blind study showed the potential of the nanocytological detection of field carcinogenesis in histologically normal prostate biopsies from patients with Gleason 6 disease as an accurate predictor of the future aggressiveness of prostate cancers. In this project we will test the hypothesis that PWS nanocytology of microscopically normal prostate tissue will be able to identify the risk of aggressive PC. We will develop a PWS nanocytology system adapted to acquire data on PC histological biopsy sections, identify new nanoscale architectural biomarkers to more accurately identify clinically significant PC, develop a robust protocol for processing and analysis of biopsies for nanocytology, and test the prediction rule in a prospective blinded study. We will enrich for African- Americans who suffer disproportionally from PC. This novel approach will be critical in bridging the era of personalized medicine to PC management. PWS nanocytology can be incorporated into AS protocols to analyze biopsies and predict subsequent progression of PC more accurately and at an earlier stage than is currently possible histologically. The approach can be coupled with existing AS protocols with no additional procedures, thus impacting upon clinical practice quickly. Our goal is that by the end of the project period, the technology will b developed, clinically tested and ready for FDA trials.