Preventing prostate cancer progression by ASC delivery of PEDF and IFNb

描述（由申请人提供）：由于前列腺癌晚期患者没有有效的治疗方法，开发治疗前列腺癌的新方法至关重要。我们仍然迫切需要新的治疗策略，尽管许多基因治疗方法已经被评估过，但临床反应仍然很差。我们的总体目标是研究开发更有效的脂肪源性间充质干细胞（ASC）基因疗法预防前列腺癌进展的潜力。我们建议研究ASCs提供的新的抗血管生成和促凋亡“细胞因子”疗法的潜力，以及它们预防前列腺肿瘤进展和刺激微环境效应细胞抗肿瘤反应的能力。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-?）在系统给药ASCs中的表达将有效预防前列腺肿瘤进展；2. ASC-交付PEDF或IFN-？将增强微环境效应细胞的募集和活性，这将有助于防止或减少肿瘤的进展。这些假设尚未得到验证，可能会导致前列腺癌新治疗方式的发展，利用新颖有效的细胞载体进行抗肿瘤基因治疗。与骨髓间充质干细胞相比，ASCs作为临床应用的治疗工具具有很高的前景，因为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扩增到治疗所需的数量。由于目前的技术允许分离自体ASCs，这可能有助于防止免疫反应，这表明ASCs作为基因传递载体可能比目前临床试验中的病毒载体更有效。我们有进行这些研究的专门知识，这将

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.