Evaluation of the Role of PSA Inhibitors in the Prevention and/or Therapy of

前列腺癌细胞，就像正常的前列腺分泌腔上皮细胞一样，产生非常高水平的 PSA。PSA的名字很贴切，因为它只由前列腺细胞高水平产生，而不是 由人类男性的任何其他正常组织大量产生。PSA是一种类凝乳杆菌胰蛋白酶 丝氨酸蛋白酶被广泛用作前列腺癌筛查和复发检测的生物标志物 在局部治疗之后，并跟踪对转移性疾病的系统治疗的反应。然而，PSA， 也是前列腺癌的有效治疗靶点。关注PSA作为生物标志物的作用 可能使“PSA”成为“生物标记物”的同义词，这也许可以解释为什么PSA没有 被认为是治疗的靶点。然而，大量的研究也表明， PSA在前列腺癌病理生物学中的作用。这些研究强调了PSA作为一种 前列腺癌的治疗靶点。因此，这个项目的假设是小分子 PSA酶活性的抑制剂将对前列腺癌局部生长具有治疗效果， 进展和/或转移。因此，这个项目的目标是识别和开发新的小型 PSA的分子抑制剂。为实现这一目标，我们提出了以下具体目标。在具体目标1中， 我们将合成一系列基于多肽的PSA抑制剂，并对其进行特异性抑制能力的评估 PSA与其他胞外蛋白酶的比较。在特定目标2中，我们将在体内评估候选抑制剂以 检测同基因PSA阳性和阴性人群的药代动力学、毒性和疗效 前列腺癌株。在具体目标3中，我们将进行相关研究，以评估这些物质的生物分布。 PSA抑制剂，并确定PSA抑制对血清PSA水平的影响。作为这一目标的一个组成部分， 我们还将评估这些PSA抑制剂的放射性标记类似物作为显像剂用于 前列腺癌。最后，我们将开发一种基于血清的测试来量化PSA抑制，可以用来 优化给药方案，最终可用于在临床上验证适当的靶向抑制 不需要组织活检的研究。这项研究与公共健康的相关性在于，PSA抑制剂 在前列腺癌的治疗和检测方面都有潜力。在本提案中，我们将执行 所需的临床前实验室研究，以确定临床测试是否合理。

Prostate cancer cells, like normal prostate secretory-luminal epithelial cells, produce very high levels of the PSA. PSA is aptly named, in that it is produced at high levels exclusively by prostate cells and is not produced in significant amounts by any other normal tissue in the human male. PSA is a chymotrypsin-like serjne protease that is used extensively as a biomarker to screen for prostate cancer, to detect recurrence following local therapies and to follow response to systemic therapies for metastatic disease. PSA, however, is also a well credentialed therapeutic target for prostate cancer. The focus on PSA's role as a biomarker has made perhaps made "PSA" synonymous with "biomarker" and this may explain why PSA has not been given consideration as a therapeutic target. However, a significant number of studies have also implicated a role for PSA in the pathobiology of prostate cancer. These studies emphasize the importance.of PSA as a therapeutic target for prostate cancer. Therefore, the hypothesis of this project is that small molecule inhibitors of PSA's enzymatic activity will have therapeutic efficacy against prostate cancer local growth, progression and/or metastases. The goal of this project, therefore is to identify and develop novel small molecule inhibitors of PSA. To achieve this goal, we propose the following Specific Aims. In Specific Aim 1, we will synthesize and evaluate a series of peptide based PSA inhibitors for their ability to specifically inhibit PSA vs. other extracellular proteases. In Specific Aim 2, we will evaluate candidate inhibitors in vivo to determine pharmacokinetics, toxicity and efficacy against isogenic PSA positive and negative human prostate cancer lines. In Specific Aim 3, we will perform correlative studies to assess biodistribution of these PSA inhibitors and to determine effect of PSA inhibition on serum PSA levels. As a component of this aim, we will also evaluate the potential of radiolabeled analogs of these PSA inhibitors as imaging agents for prostate cancer. Finally, we will develop a serum based test to quantify PSA inhibition that can be used to optimize dosing regimens and that ultimately could be used to validate adequate target inhibition in clinical studies without requiring tissue biopsy. The relevance of this research to public health is that PSA inhibitors have potential in both the treatment and detection of prostate cancer. In this proposal we will perform the required preclinical laboratory studies needed to determine if clinical testing is justified.