Tissue Specific Gene Therapy for Human Prostate Cancer

人类前列腺癌的组织特异性基因治疗

• 批准号: 7426332
• 负责人: Chinghai Kao
• 金额: $ 26.5万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7426332
• 关键词: Ablation; Address; Adenovirus Vector; Adenoviruses; Androgens; Apoptosis Promoter; B-Lymphocytes; Binding; Biological Assay; Blood; CMV promoter; Cells; Clinical Trials; Complementary DNA; Contracts; Diagnosis; Endothelium; Enhancers; Exhibits; Funding; Genes; Glutamate Carboxypeptidase II; Goals; Green Fluorescent Proteins; Growth; Hand; Harvest; Hematopoietic; Herpes Simplex Infections; Human; In Vitro; Injection of therapeutic agent; Introns; Kidney; Life; Liver; Luciferases; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Medical; Metastatic Lesion; Modeling; Mus; Mutation; Neoplasm Metastasis; Neurons; Numbers; Organ; Osteocalcin; Patients; Phase; Pilot Projects; Prostate; Prostate-Specific Antigen; Recombinants; Regulation; Reporter; Reporting; Research Personnel; Specificity; Spleen; Structure of base of prostate; T-Lymphocyte; TK Gene; Testing; Therapeutic Agents; Tissues; Treatment Efficacy; United States; Upper arm; Upstream Enhancer; Virus; Work; airway epithelium; androgen independent prostate cancer; base; bone; cancer cell; cell killing; cell type; gene therapy; hormone refractory prostate cancer; human tissue; in vivo; killings; macrophage; men; neoplastic cell; novel; prevent; programs; promoter; tissue culture; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Currently, androgen ablation is the most effective therapy available for advanced prostate cancers. However, androgen ablation does not prevent prostate cancer progression to the lethal androgen-independent (AI) state. The goal of this proposal is to develop a gene therapy strategy for AI prostate cancer based on our study of the regulation of prostate specific antigen (PSA) and prostate specific membrane antigen (PSMA) promoter/enhancer in AI prostate cancer cells. PSA expression is upregulated by androgens. In contract PSMA expression is down regulated by androgens. We believe that PSA and PSMA promoters likely function weakly in patients receiving androgen-ablation therapy due to the presence of low levels of androgen and AR mutation or amplification that will partially activate PSA promoter and suppress PSMA promoter. In the previous funding period, by detecting and deleting silencers, we identified strong central enhancer cores from PSA and PSMA enhancers, called AREc3 and PSME(del2). A combination of AREc3 and PSME(del2), called PSES, demonstrated strong prostate-specific activity regardless of androgen status. This observation suggests that AREc3 and PSME(del2) can work together and compensate each other's activity in patients with AI prostate cancer. We propose to investigate the tissue-specific activity of AREc3 and PSME(del2) when placed adjacent to each other in adenoviral vectors. We constructed a recombinant adenovirus, Ad-PSES-Luc, carrying luciferase reporter under the control of PSES. We will test its tissue-specific activity in PSA/PSMA-positive prostate cancer cells, PSA/PSMA-negative prostate cancer cells, non-prostatic cancer cells and primary human tissue cultures from different organs. We hypothesize that AREc3/PSME(del2) or PSES can control adenovirus replication in a prostate cancer-specific manner by controlling adenoviral E1a and E1b expression. We will construct several AREc3/PSME(del2) or PSES based-prostate-restricted replicative adenoviruses (PRRAs) to test this hypothesis. The majority of prostate cancers compose both PSA/PSMA positive and negative cells that might limit the therapeutic efficacy of our PRRA. To overcome this potential hurdle, we propose to incorporate a tumor specific apoptosis inducer, Trail, into our PRRA. We hypothesize that Trail can eliminate neighboring PSA/PSMA negative tumor cells when expressed by PSA/PSMA positive tumor cells. We will generate Trail-armed adenovirus and a chimeric tumor model, composing both PSA/PSMA positive and negative tumor cells, to test this hypothesis. We will potentially provide a novel agent to treat androgen-independent prostate cancer at the end of this project.

描述（由申请人提供）：目前，雄激素消除是治疗晚期前列腺癌最有效的疗法。然而，雄激素消除并不能阻止前列腺癌进展至致命的雄激素非依赖性（AI）状态。本提案的目标是基于我们对 AI 前列腺癌细胞中前列腺特异性抗原 (PSA) 和前列腺特异性膜抗原 (PSMA) 启动子/增强子的调节研究，开发 AI 前列腺癌的基因治疗策略。 PSA 表达受雄激素上调。在合同中，PSMA 表达受到雄激素的下调。我们认为，PSA 和 PSMA 启动子在接受雄激素消融治疗的患者中可能功能较弱，因为存在低水平的雄激素和 AR 突变或扩增，这将部分激活 PSA 启动子并抑制 PSMA 启动子。在之前的资助期间，通过检测和删除消音器，我们从 PSA 和 PSMA 增强子中识别出强大的中央增强子核心，称为 AREc3 和 PSME(del2)。 AREc3 和 PSME(del2) 的组合， 称为 PSES，无论雄激素状态如何，都表现出很强的前列腺特异性活性。这一观察结果表明，在 AI 前列腺癌患者中，AREc3 和 PSME(del2) 可以协同工作并相互补偿彼此的活性。我们建议研究 AREc3 和 PSME(del2) 在腺病毒载体中彼此相邻放置时的组织特异性活性。我们构建了重组腺病毒 Ad-PSES-Luc，在 PSES 的控制下携带荧光素酶报告基因。我们将在PSA/PSMA阳性前列腺癌细胞、PSA/PSMA阴性前列腺癌细胞、非前列腺癌细胞和来自不同器官的原代人体组织培养物中测试其组织特异性活性。我们假设 AREc3/PSME(del2) 或 PSES 可以通过控制腺病毒 E1a 和 E1b 的表达来以前列腺癌特异性方式控制腺病毒复制。我们将构建几种基于 AREc3/PSME(del2) 或 PSES 的前列腺限制性复制腺病毒 (PRRA) 来检验这一假设。大多数前列腺癌由 PSA/PSMA 阳性和阴性细胞组成，这可能会限制我们 PRRA 的治疗效果。为了克服这一潜在障碍，我们建议将肿瘤特异性细胞凋亡诱导剂 Trail 纳入我们的 PRRA 中。我们假设当 PSA/PSMA 阳性肿瘤细胞表达时，Trail 可以消除邻近的 PSA/PSMA 阴性肿瘤细胞。我们将生成 Trail-armed 腺病毒和嵌合肿瘤模型，由 PSA/PSMA 阳性和阴性肿瘤细胞组成，以检验这一假设。在该项目结束时，我们有可能提供一种治疗雄激素非依赖性前列腺癌的新药。