Preventing prostate cancer progression by ASC delivery of PEDF and IFNb

通过 ASC 输送 PEDF 和 IFNb 预防前列腺癌进展

• 批准号: 8446315
• 负责人: Marxa L Figueiredo
• 金额: $ 18.67万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446315
• 关键词: Address; Adenovirus Vector; Adenoviruses; Adipose tissue; Antitumor Response; Apoptosis; Autologous; Bioluminescence; Bone Marrow; Cancer Patient; Cell Differentiation process; Cell Therapy; Cells; Clinical; Clinical Research; Clinical Trials; Cytokine Gene; Data; Detection; Development; Disease; Distant Metastasis; Dose; Effectiveness; Effector Cell; Endothelial Cells; Enzymes; Firefly Luciferases; Gene Delivery; Goals; Growth; Half-Life; Image; Immune; Infection; Innovative Therapy; Interferon-beta; Interferons; Link; Luc Gene; Macular degeneration; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Medicine; Mesenchymal Stem Cells; Metastatic to; Methods; Modality; Modeling; Monitor; Morbidity - disease rate; Mus; Neoplasm Metastasis; Oncogenes; Patients; Phenotype; Population; Probability; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Publishing; Reaction; Recombinant Cytokines; Recombinant Proteins; Recruitment Activity; Renilla; Reporter; Resources; Role; S Phase Arrest; Secondary to; Signal Transduction; Site; Staging; Structure of base of prostate; Systemic Therapy; Techniques; Testing; Therapeutic; Time; Toxic effect; Toxicology; Transgenic Model; Translating; Viral Vector; Work; antiangiogenesis therapy; antitumor agent; base; bioluminescence imaging; chemokine; clinical application; college; cytokine; cytokine therapy; design; effective therapy; gene therapy; immune activation; immunogenic; immunogenicity; immunoregulation; improved; in vivo; insight; intravenous administration; neoplastic cell; novel; novel strategies; novel therapeutics; outcome forecast; pigment epithelium-derived factor; pre-clinical; prevent; prostate carcinogenesis; research study; response; sensor; success; tool; tumor; tumor growth; tumor progression; tumorigenesis; vector

DESCRIPTION (provided by applicant): Developing new approaches for therapy of prostate cancer is critical as there is no effective treatment for patients in the advanced stages of this disease. There remains a critical need for novel therapeutic strategies, and although many gene therapy approaches have been evaluated, clinical responses remain poor. Our overall objective is to examine the potential of developing more effective adipose- derived mesenchymal stem cell (ASC)-based gene therapies for preventing prostate cancer progression. We propose to examine the potential of new antiangiogenesis and proapoptotic 'cytokine' therapies delivered by ASCs and their ability both to prevent prostate tumor progression and also to stimulate antitumor responses by microenvironment effector cells. The specific hypotheses we propose to address include: 1. Expression of antitumor cytokine gene therapies (PEDF or IFN-?) in systemically-delivered ASCs will be effective in preventing prostate tumor progression; 2. ASC- delivered PEDF or IFN-? will enhance recruitment and activity of microenvironment effector cells, which will aid in preventing or reducing tumor progression. These hypotheses remain untested and could result in the development of novel therapeutic modalities for prostate cancer, utilizing novel and effective cellular-based vehicles for antitumor gene therapy. ASCs hold high promise as therapeutic tools with clinical applications since, compared to bone marrow mesenchymal stem cells, they can be isolated using simpler methods and are much more easily expanded at early passage numbers to quantities required for therapy. And since current techniques allow isolation of autologous ASCs, this could help prevent immune reaction, suggesting that ASCs could be far more efficient as a gene delivery vehicle than viral vectors currently in clinical trials. We have the specific expertise to carry out these studies, which will not only provide new insights into the mechanisms of PEDF and IFN-? as prostate cancer gene therapies, but also insights into their real-time activation of immune-effectors in vivo. The experiments proposed have a high probability of success because we have excellent models of prostate cancer progression in place, the access to new and highly efficient bioluminescence enzymes and vectors to monitor the localization of different cell populations, and all other collaborative and institutional resources necessary to complete the tasks.

描述（由申请人提供）：开发治疗前列腺癌的新方法至关重要，因为对于这种疾病的晚期患者没有有效的治疗方法。仍然迫切需要新的治疗策略，虽然许多基因治疗方法已被评估，临床反应仍然很差。我们的总体目标是研究开发更有效的基于脂肪来源间充质干细胞（ASC）的基因疗法来预防前列腺癌进展的潜力。我们建议研究新的抗血管生成和促凋亡的“细胞因子”疗法的潜力，通过ASCs和他们的能力，以防止前列腺肿瘤的进展，也刺激抗肿瘤反应的微环境效应细胞。我们提出的具体假设包括：1。抗肿瘤细胞因子基因疗法（PEDF或IFN-？）的表达在全身性递送的ASC中，将有效预防前列腺肿瘤进展; 2. ASC-递送的PEDF或IFN-？将增强微环境效应细胞的募集和活性，这将有助于预防或减少肿瘤进展。这些假设仍然未经检验，并可能导致前列腺癌的新的治疗方式的发展，利用新的和有效的细胞为基础的抗肿瘤基因治疗的车辆。ASCs作为临床应用的治疗工具具有很高的前景，因为与骨髓间充质干细胞相比，它们可以使用更简单的方法分离，并且更容易在早期传代数量扩增到治疗所需的数量。由于目前的技术允许分离自体ASC，这可能有助于防止免疫反应，这表明ASC作为基因递送载体可能比目前临床试验中的病毒载体更有效。我们拥有开展这些研究的专门知识， 不仅提供了新的见解PEDF和IFN-？作为前列腺癌基因疗法，但也了解他们的实时激活免疫效应在体内。所提出的实验有很高的成功概率，因为我们有很好的前列腺癌进展模型，可以获得新的高效生物发光酶和载体来监测不同细胞群的定位，以及完成任务所需的所有其他合作和机构资源。