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

PSA 抑制剂在预防和/或治疗中的作用评估

• 批准号: 7468660
• 负责人: JOHN ISAACS
• 金额: $ 26.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468660
• 关键词: Ablation; American; Androgen Receptor; Androgens; Biodistribution; Biological Markers; Biopsy; Caring; Cells; Cessation of life; Clinical Research; Correlative Study; Credentialing; Detection; Development; Disease; Disseminated Malignant Neoplasm; Dose; Drug Kinetics; Endopeptidases; Epithelial Cells; Evaluation; Goals; Growth; Image; Laboratory Study; Local Therapy; Malignant neoplasm of prostate; Names; Neoplasm Metastasis; Normal tissue morphology; Numbers; Paper; Peptide Hydrolases; Peptides; Prevention; Principal Investigator; Prostate; Prostate-Specific Antigen; Public Health; Radiolabeled; Recurrence; Relapse; Research; Role; Screening for Prostate Cancer; Series; Serine Protease; Serum; Standards of Weights and Measures; Structure of base of prostate; Systemic Therapy; Testing; Tissues; Toxic effect; Treatment Efficacy; Treatment Protocols; Writing; analog; base; cancer cell; chemotherapeutic agent; chymotrypsin; docetaxel; extracellular; hormone refractory prostate cancer; human male; in vivo; inhibitor/antagonist; men; novel; pre-clinical; programs; radiotracer; research clinical testing; response; small molecule; therapeutic target

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.

前列腺癌细胞，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。前列腺特异性抗原（PSA）这个名字很恰当，因为它只由前列腺细胞产生高水平的PSA， 由人类男性的任何其他正常组织大量产生。PSA是一种胰凝乳蛋白酶样 丝氨酸蛋白酶被广泛用作筛选前列腺癌的生物标志物，以检测复发 在局部治疗后和对转移性疾病的全身治疗的反应后。然而，PSA 也是前列腺癌的公认治疗靶点。PSA作为生物标志物的作用 可能使“PSA”成为“生物标志物”的同义词，这可以解释为什么PSA没有被 考虑作为治疗靶点。然而，大量的研究也表明， PSA在前列腺癌病理学中的作用。这些研究强调了PSA作为一种 前列腺癌的治疗靶点。因此，本项目的假设是， PSA酶活性的抑制剂对前列腺癌局部生长具有治疗功效， 进展和/或转移。因此，该项目的目标是确定和开发新的小型 PSA的分子抑制剂。为实现这一目标，我们提出以下具体目标。具体目标1、 我们将合成并评价一系列基于肽的PSA抑制剂，以检测它们特异性抑制 PSA与其他细胞外蛋白酶。在具体目标2中，我们将在体内评估候选抑制剂， 确定对同基因PSA阳性和阴性人的药代动力学、毒性和疗效 前列腺癌细胞系在具体目标3中，我们将进行相关研究，以评估这些药物的生物分布 PSA抑制剂，并测定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的潜力， 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， 优化给药方案，最终可用于验证临床中的充分靶向抑制 无需组织活检的研究。这项研究与公共卫生的相关性在于， 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 确定临床试验是否合理所需的临床前实验室研究。