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.
Developing new approaches for preventing prostate cancer progression is highly relevant to prostate cancer patients, as there are no effective treatments for the advanced stages of the disease. Our overall objective is to examine the potential of developing more effective cell-based gene therapies for preventing prostate cancer progression using adipose-derived mesenchymal stem cells (ASCs) as cellular vehicles. We propose that expression of antitumor cytokine gene therapies (PEDF or IFN-?) from ASCs will be effective in preventing prostate tumor progression and in enhancing recruitment and activation of microenvironment immune effector cells that will aid in reducing tumor growth.
|Zolochevska, Olga; Shearer, Joseph; Ellis, Jayne et al. (2014) Human adipose-derived mesenchymal stromal cell pigment epithelium-derived factor cytotherapy modifies genetic and epigenetic profiles of prostate cancer cells. Cytotherapy 16:346-56|