MSC Delivery of PSA Activated Pro-Aerolysin for Prostate Cancer

MSC 输送 PSA 激活的气溶素原治疗前列腺癌

• 批准号: 10264514
• 负责人: JOHN Tod ISAACS
• 金额: $ 21.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264514
• 关键词: Ablation; Allogenic; Androgens; Award; Biological; Blood; Bone Marrow; Cells; Characteristics; Clinical; Clinical Trials; Data; Development; Disease; Documentation; Early treatment; Engineering; Equus caballus; Ethical Issues; FDA approved; Foundations; Funding; Genetic Engineering; Growth; Home environment; Homing; Human; Inflammatory; Infusion procedures; Institutional Review Boards; Intravenous infusion procedures; Laboratories; Literature; Local Therapy; Malignant Neoplasms; Malignant neoplasm of prostate; Mesenchymal Stem Cells; Metastatic Prostate Cancer; Monitor; New Agents; Patients; Peptide Hydrolases; Phase; Production; Prostate; Prostate Cancer therapy; Prostate-Specific Antigen; Prostatectomy; Prostatic Diseases; Proteins; Protocols documentation; Publishing; Recombinants; Regenerative Medicine; Research; Safety; Series; Site; Standardization; Stream; Symptoms; Systemic Therapy; Testing; Therapeutic; Therapeutic Agents; Tissue Harvesting; Toxic effect; Treatment Efficacy; Universities; Xenograft procedure; aerolysin; base; bone; cancer cell; clinical development; cost; design; digital; effective therapy; hormone therapy; in vivo; male; man; medical schools; men; prevent; prostate cancer cell; reduce symptoms; research clinical testing; subcutaneous

Based upon substantial published literature from multiple groups, as well as unpublished studies to be presented from the applicants' laboratories, there is strong documentation that bone marrow-derived Mesenchymal Stem Cells are released into the blood stream and home to sites of primary and metastatic prostate cancer driven by the inflammatory microenvironment characteristically present within prostate cancer's stromal compartment. Thus, the hypothesis of this project is that allogeneic human bone marrow-derived MSCs (hbMSCs) can be used as a cell-based targeting vehicle to selectively deliver (i.e., home) therapeutic agents to sites of prostate cancer, thus sparing host toxicity. In this application, data will be presented validating the rationale for this "Trojan Horse" approach in which allogeneic hbMSCs are genetically-engineered to express a recombinant pro-aerolysin protein protoxin. While initially inactive, this protoxin is engineered to be selectively hydrolyzed to a picoMolar killing molecule by the enzymatic activity of a protease [i.e.. Prostate Specific Antigen (PSA)] which is only enzymatically active in high levels within the stroma at sites of prostate cancer. Since hbMSCs are being tested in clinical trials for regenerative medicine and recombinant PSA activated pro-aerolysin is in clinical testing as local therapy for prostate diseases, the proposed use of PSA-activated pro-aerolysin expressing hbMSCs could rapidly enter clinical development as systemic therapy for lethal metastatic prostate cancer based upon the successful completion of the following specific aims.

根据来自多个小组的大量已发表的文献，以及申请者的实验室将提交的未发表的研究，有强有力的文献表明，骨髓来源的间充质干细胞被释放到血流中，并在前列腺癌间质内特有的炎性微环境的驱动下，成为前列腺癌原发和转移部位的所在地。因此，本项目的假设是，异基因人骨髓间充质干细胞(HbMSCs)可以作为基于细胞的靶向载体，选择性地将治疗药物输送(即，国内)到前列腺癌部位，从而减少宿主的毒性。在本应用程序中，将提供数据来验证这种“特洛伊木马”方法的原理，在这种方法中，同种异体hbMSCs 基因工程表达重组前溶气素蛋白原毒素。虽然最初没有活性，但这种原毒素被设计为通过蛋白酶的酶活性选择性地水解为皮摩尔杀伤分子[即。前列腺特异性抗原(PSA)]，仅在前列腺癌部位的间质中有高水平的酶活性。由于hbMSCs正在进行再生医学的临床试验，重组PSA激活的溶气素原作为前列腺癌的局部治疗正在进行临床测试，因此，基于以下特定目标的成功完成，表达hbMSCs的PSA激活的溶气素原有望迅速进入临床开发，作为对致命转移性前列腺癌的系统治疗。