Zinc-Based Early Detection of Prostate Cancer

描述（由申请人提供）：在I期研究中，我们发现我们对前列腺液中游离锌的测量是前列腺癌的一个有前景的临床指标。事实上，在我们的两项试点研究和一项先前发表的研究中，前列腺液锌评分给出了0.79、0.92和0.99的受试者工作曲线下面积（AUROC），用于检测活检证实的前列腺腺癌。我们的检查是非侵入性的，只需要在直肠前列腺检查和简短的前列腺按摩过程中从尿道口取几滴前列腺液。锌的测量是快速，廉价，容易，精确。我们的第二阶段研究有两个组成部分。在研究IIA中，我们将增加样本量，以更好地估计检测的灵敏度和特异性。我们将从精心挑选的大约100名预计患有前列腺癌的男性和大约100名预计无癌症的男性样本中收集前列腺液样本。在组织病理学确认所有男性均为腺癌或不存在腺癌后，将进行接受者工作曲线分析，以确定通过测量前列腺液中的锌检测腺癌的灵敏度、特异性和总曲线下面积（AUROC）。这项研究将显示锌测试对检测前列腺癌有多有用。本研究中的受试者将是（i）计划接受膀胱切除术的男性，（ii）计划接受膀胱切除术的男性，（iii）计划接受饱和（64芯）穿刺活检的男性和（iv）计划接受常规活检的男性。在研究IIB中，我们将确定哪些前列腺疾病伴随着锌螯合和分泌的丧失。因此，我们将从研究IIA中的受试者的前列腺中取出组织切片，用H&E和（在某些情况下）疾病定义蛋白的抗体对其进行染色。将在切片的数字图像上标记具有特定前列腺病理学的区域，例如PIA（增生性炎性萎缩）、PIN（前列腺上皮内瘤变）或腺癌，然后在X射线荧光和锌组织荧光显微镜下对相邻切片进行成像，以分别显示元素锌和游离锌的分布。通过数字叠加将经典组织学与锌图进行比较，将显示锌螯合（以及因此分泌）在每种不同类型和病理阶段中的变化。文献中的数据表明，锌的螯合和分泌在PIN中受到抑制，并且在腺癌附近的健康外观的腺泡中受到抑制，这表明场效应。如果我们的工作证实了这一点，这就可以解释即使是相对较小的腺癌也会明显抑制腺体的锌分泌。在美国，每年约有150万例前列腺活检，仅发现约30万例癌症。尽管如此，仍有约3万名男性死于晚期癌症，无法进行有效治疗。我们相信我们的锌测试可以更早，更确定地检测潜在的侵袭性癌症，从而挽救生命。公共卫生叙述：这一II期SBIR旨在确定前列腺癌锌试验的敏感性和特异性。该测试测量按摩前列腺液中的锌，只需要大约60秒就可以得到液体，大约60秒就可以在桌面上进行测量，5000美元的仪器。该测试旨在补充其他测试，包括PSA和DRE。因为锌福尔斯在癌症中下降，但在BPH中不下降，锌测试有可能区分这两种情况。

DESCRIPTION (provided by applicant): In Phase I we showed that our measurement of free zinc in expressed prostatic fluid is a promising clinical indicator of prostate cancer. Indeed, in our two pilot studies and one prior published study, prostatic fluid zinc scores gave areas under the receiver operating curve (AUROC) of .79, .92, and .99 for detecting biopsy-confirmed prostatic adenocarcinoma. Our test is non-invasive, requiring only a few drops of prostatic fluid obtained from the urethral meatus during a rectal prostate examination with brief prostate massage. The zinc measurement is fast, cheap, easy, and exquisitely accurate. Our Phase II study has two components. In Study IIA we will increase our sample size to better estimate the sensitivity and specificity of our test. We will collect samples of prostatic fluid from a carefully selected sample of approximately 100 men expected to have prostate adenocarcinoma and approximately 100 men expected to be cancer free. Upon histopathological confirmation of adenocarcinoma or the absence of adenocarcinoma in all men, a receiver operating curve analysis will be conducted to determine the sensitivity, specificity and overall area under the curve (AUROC) for the detection of adenocarcinoma by the measurement of zinc in prostatic fluid. This study will show how useful the zinc test is for detecting prostate cancer. The subjects in this study will be (i) men scheduled for prostatectomy (ii) men scheduled for cysto-prostatectomy (iii) men scheduled for saturation (64 core) needle biopsy and (iv) men scheduled for conventional biopsy. In Study IIB we will establish which prostatic disease conditions are accompanied by the loss of zinc sequestering and secretion. Thus, we will take tissue sections from the prostate glands of the subjects in Study IIA, stain them with H&E and (in some cases) antibodies to disease- defining proteins. Regions with specific prostatic pathology such as PIA (proliferative inflammatory atrophy), PIN (prostatic intraepithelial neoplasia) or adenocarcinoma will be marked on digital images of the sections, then adjacent sections will be imaged in X-RAY fluorescence and zinc histofluorescence microscopy to show the distribution of elemental and free zinc , respectively. Comparison of the classical histology with the zinc maps by digitally superimposing them will show how zinc sequestration (and therefore secretion) changes in each of the different types and stages of pathology. Data in the literature indicate that zinc sequestration and secretion are suppressed in PIN and suppressed in healthy-appearing acini that are near an adenocarcinoma, suggesting a field effect. If confirmed by our work, this would explain how even relatively small adenocarcinomas markedly suppress zinc secretion of the gland. Every year in the US about 1,500,000 prostate biopsies are done, revealing only about 300,000 cancers. Still, about 30,000 men die from cancers too advanced for effective treatment. We believe our zinc test could allow earlier and more certain detection of potentially aggressive cancers, thus saving lives. PUBLIC HEALTH NARAVTIVE: This Phase II SBIR is designed to determine the sensitivity and specificity of a zinc test for prostate cancer. The test measures zinc in massage-expressed prostatic fluid, and it only takes about 60 sec to get the fluid and about 60 sec to make the measurement on a table-top, $5000 instrument. The test is intended to supplement other tests, including the PSA and DRE. Because the zinc falls in cancer but does not fall in BPH, the zinc tests has the potential to distinguish these two conditions.