Validation of Digital Morphometry for Cancer Risk in Benign Prostate Biopsies

描述（由申请人提供）：在PCPT和REDUCE试验中，非那雄胺和度他雄胺分别使前列腺癌（PCa）的检出率显著降低23%和25%，因此确定51-还原酶抑制剂（5ARI）是经证明可作为PCa化学预防剂的第一类药物。这些药物的实际疗效因人而异，即使考虑到遵守规定的剂量。更好地理解对5ARI化学预防的敏感性的基础将：1）为开发利用这种既定机制的耐受性更好和更有效的药物铺平道路，2）使临床医生能够靶向有反应的男性，从而降低终身剂量的成本和发病率，3）验证特定的组织生物标志物作为II期试验的替代终点。我们基于直接DNA染色的初步数据表明，表征5ARI反应的核形态特征也可以定义预测活检阴性的未经治疗男性中PCa的场效应。2009年完成的REDUCE为解决这些问题提供了一个独特的机会，因为采集了研究期间的中期活检样本（第2年和第4年必须采集）。以前的研究表明，5ARI（在短期内以较高剂量）在良性前列腺中产生类似不完全萎缩的变化。我们的总体目标是应用最先进的成像方法，将机器学习用于模式识别和多光谱分析，以开发和验证良性组织中的中间终点生物标志物，其表征对5ARI化学预防的反应以及活检阴性男性中PCa的风险。我们将从随机抽取的具有不同结局的REDUCE参与者中获得第2年的切片和组织块。目的1：确定度他雄胺（与安慰剂相比）对良性组织核和结构特征的影响。目标二：为了确定多变量治疗反应评分是否在使用度他雄胺时发生PCa的受试者与未发生PCa的受试者之间存在差异，目的3：确定良性活检中的核表型与未治疗男性中PCa风险升高的后续风险之间的关联程度。总之，我们将使用3种技术来评估细胞形态学：a）基于核大小、形状和纹理的形态学评分，B）通过量子点成像表达p300和核仁素（两种对染色质模式和核形态有主要影响的蛋白质）和c）构建特征的映射（例如，上皮面积和高度）。这将是第一项将5ARI的细胞形态学效应与随后的癌症发生联系起来的工作，5ARI以化学预防剂量水平给予很长时间。这些结果将对化学预防研究和临床实践产生影响，包括大量美国男性在前列腺活检阴性后仍处于危险之中。

DESCRIPTION (provided by applicant): In the PCPT and REDUCE trials, finasteride and dutasteride significantly reduced the detection of prostate cancer (PCa) by 23 and 25% respectively, and thus established that 51-reductase inhibitors (5ARI) are the first class of drugs proven as chemopreventive agents for PCa. The actual efficacy of these drugs varies among individuals, even after considering compliance with the prescribed dosage. Better understanding of the basis for sensitivity to 5ARI chemoprevention will: 1) pave the way for development of better-tolerated and more effective agents that exploit this established mechanism, 2) allow clinicians to target responsive men, thus reducing the cost and morbidity of life-long dosage, and 3) validate specific tissue biomarkers as surrogate endpoints for Phase II trials. Our preliminary data based on direct DNA staining suggest that nuclear morphometric features that characterize 5ARI response may also define a field effect that predicts PCa in untreated men with negative biopsies. REDUCE, which was completed in 2009, provides a unique opportunity to address these questions because intermediate, on-study biopsy samples (mandatory at Years 2 and 4) were collected. Previous research indicated that 5ARIs (at higher doses for short periods) produce changes in benign prostate that resemble incomplete atrophy. Our overall goal is to apply cutting- edge imaging approaches, incorporating machine-learning for pattern recognition and multispectral analysis, to the development and validation of intermediate endpoint biomarkers in benign tissue that characterize the response to 5ARI chemoprevention as well as the risk of PCa among men with negative biopsies. We will obtain Year 2 slides and tissue blocks from a random sample of REDUCE participants with various outcomes. Aim 1: To determine the effects of dutasteride (vs. placebo) on both nuclear and architectural features in benign tissue. Aim 2: To determine whether a multivariable treatment-response score differs between subjects who develop PCa while on dutasteride and those who do not, and, Aim 3: To determine the magnitude of association between nuclear phenotype in benign biopsies, and subsequent risk of PCa in untreated men at elevated risk. Altogether, we will use 3 techniques to assess cytomorphology: a) a morphometric score based on nuclear size, shape and texture, b) expression -via quantum dot imaging - of p300 and nucleolin (two proteins with major effects on chromatin pattern and nuclear morphology) and c) mapping of architectural features (e.g., epithelial area and height) via trainable software. This will be the first work to relate the cytomorphological effects of a 5ARI, given at a chemopreventive dose level for a lengthy period, to subsequent cancer occurrence. The results will have implications for chemoprevention research and clinical practice, including the large number of U.S. men who remain at risk following a negative prostate biopsy.