Projects / Programmes
New approaches of tumor radiosenzibilization with gene therapy
| Code |
Science |
Field |
Subfield |
| 3.04.00 |
Medical sciences |
Oncology |
|
| Code |
Science |
Field |
| B200 |
Biomedical sciences |
Cytology, oncology, cancerology |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
antiangiogenic gene therapy, endoglin, gene electrotransfer, plasmid DNA, RNA interference technology, tissue specific promoter
Researchers (21)
Organisations (2)
Abstract
The proposed project is aimed at developing new gene therapy approach, based on endoglin silencing using RNA interference technology, by gene electrotransfer as delivery system. Its antiangiogenic action and antitumor effectiveness on experimental tumor models in mice will be studied, as well as its possible implementation in combined therapy with tumor irradiation.
Antiangiogenic therapeutic approaches are nowadays well established in oncology, targeting VEGF and EGF, predominantly using monoclonal antibodies and small molecules. With development of gene therapy the antiangiogenic approach is possible also by introducing siRNA molecules, or shRNA. With this approach silencing of the specific molecules is possible in specific target tissue. Endoglin is a co-receptor of TGF-β, involved in tumor angiogenesis, and therefore a potential target in tumor treatment. Some reports already indicated that targeting endoglin has antitumor and antiangiogenic effects on tumors, but the studies have not explored the potential of gene therapy using RNA interference technology against endoglin expression. Preparation of plasmid with tissue specific promoters for endothelin gene and encoding shRNA against endoglin could make the therapy even more specific and possibly also safer. Therefore in our study we aim to explore this therapeutic approach using electroporation based delivery system in treatment of tumors in mice and to explore the effects on molecular and tissue level by histology. Furthermore, we intend to monitor the vascular effects in tumors in dorsal window chamber, as well as tumor perfusion changes.
Due to a potential of antiangiogenic approaches in combined treatment, we will explore the possible implementation of gene therapy against endoglin in combined treatment with tumor irradiation. Investigated will be the effects of single or multiple gene electrotransfers, combined with single tumor irradiation. The approach will be aimed at treatment of tumors in vascular phase of growth, the antitumor effectiveness and as well normal tissue damage in irradiation fields will be monitored, to determine therapeutic index of combined treatment.
Expected results will be on the level of basic knowledge, by exploring new therapeutic target using gene therapy approach alone or combined with radiation therapy that could be swiftly translated into the therapeutic approach in the clinics.
Significance for science
The aim of the program was to develop a new gene therapy approach that combines endogenous silencing with RNA interference technology and gene electrotransfer as a delivery method. Gene therapy is an innovative and rapidly growing treatment approach for cancer. Gene electrotransfer has now been recognized to have potential as a delivery system, predominantly because of its safety compared to viral vectors. In our studies we developed plasmids encoding therapeutic molecules that would give antiangiogenic or immunomodulatory effect. By further development and evaluation of the effectiveness, we foster this treatment approach into translational research, especially as we proved it to be safe, feasible and effective in combination with radiotherapy. Furthermore, gene electrotransfer has already been translated into veterinary oncology, where we have been the leading actors so far. Therefore, on the basis of good pre-clinical work, we have contributed to the development of this technology, which can be further implemented in treatment of animals, in Slovenia as well as internationally.
Significance for the country
Cancer incidence is steadily increasing, and the treatment of cancer patients is a growing financial burden for national health security systems. Specifically, because new targeted therapies are costly, however their effectiveness is below expectation. The impact of new therapeutic approach on health care system costs is an important factor in providing not only efficient but also less resource-intensive treatment approaches. With development of new therapeutic approaches such as gene electrotransfer, we developed a new technology for treatment of cancer, which is based on electroporation. The technology is relatively cheap and is applicable for drug delivery, and through its development, it can replace or complement some of the existing, more costly therapeutic approaches. Indirect impact of this project for society was the inclusion of the project in postgraduate studies in Slovenia as well as on the international level. According to this, doctoral students were involved in the project and the results were presented in their doctoral thesis. The results were regularly presented at national and international conferences, and through this we promoted the Slovenian knowledge, and were able to integrate into the international collaborations.
Most important scientific results
Annual report
2014,
2015,
final report
Most important socioeconomically and culturally relevant results
Annual report
2014,
2015,
final report
