Projects / Programmes
Apoptoza tumorskih celic kot tarča kemoterapevtikov (Slovene)
| Code |
Science |
Field |
Subfield |
| 1.09.00 |
Natural sciences and mathematics |
Pharmacy |
|
| Code |
Science |
Field |
| 3.05 |
Medical and Health Sciences |
Other medical sciences |
Researchers (8)
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0105 |
National Institute of Biology |
Ljubljana |
5055784 |
13,283 |
Significance for science
With respect to a vast body of literature and our previous work, we believe that the monitoring of selective activities of cathepsins (Cats) such as CatB, using non-invasive in vivo methods would represent a useful prognostic factor for brain tumours’ therapy. Therefore, we developed the tools – activity based fluorescent probes, detecting active cysteine cathepsins to label and inhibit cathepsins selectively. The probes, which we have developed, display highly improved selectivity for CatB and CatL as do the existing available probes published in the past. This is the key success of this project, enabling the studies of GBM apoptosis, induced by cytostatics.
Additionally, we have presented a proof of principle that lowering CatL activity with these inhibitors could, because of their synergistic activity with known cytotoxic drugs i.e. Arsenite, be a useful strategy when combined with the chemotherapy. As we succeeded in proving the enhanced apoptotic activity in the tumour cells arising from the combined treatment consisting of CatL probes and chemotherapeutics, we feel confident to ambitiously predict, that targeting CatL by these highly selective probes in tumours during chemotherapy, would indeed enhance the selectivity of tumour cells’ response to therapy. This would allow for a decrease of the applicable therapeutic doses of toxic drugs, resulting in elimination of the toxic side effects and thereby increased the quality of brain tumour patients’ life.
Besides the above the CatL markers also represent good tools for localising active forms of CatL at cellular and sub-cellular level. Since increased expression of CatL was observed only in tumour cells, the CatL selective probes would be of a great help to clinicians during surgery for tumour site localisations and successful complete brain tumour resection. Our results also indicate that with the use of those selective cathepsins' probes, one could successfully follow malignant tumour cells that are invading into normal brain parenchyma. By utilizing labelling with CatL selective probes at the resection site, the neurosurgeons would be able define the exact borders of the invasive brain tumour and thereby be able to proceed with much more focused local therapy (for example with X-rays and »gamma knife«). Our results are based on a model of brain tumours - glioblastoma, which is one of the incurable and most aggressive tumours, where surgical resection of it poses the highest danger for damaging the surrounding tissue crucial for human vital functions.
By studying the usefulness and applicability of highly selective cathepsins’ probes for detection and cell death induction in GBM cells and primary tumour tissue, we have demonstrated the effect of CatL on a GBM CD133+ stem-like cells, which in fact represent a new target for GBM therapy, since GBM stem cells removal is believed to efficiently prevent the relapse of the disease.
Significance for the country
The incidence of cancer is increasing in Slovenia, and frightfully the incidence of brain tumours is increasing also in younger generation. Glioblastomas are therefore becoming more often diagnosed also within Slovene population and despite advanced research in Slovenia and worldwide, the survival of glioblastoma patients remains rather poor (only 13 months). The key step in cancer diagnosis could be acheived by the identification of specific tumour markers, which would enable early detection, correct diagnosis and control over the spread of a disease, thereby increasing cancer patients’ survival.
The selective CatL probes, which we synthesized would enable monitoring of malignant tumour cells, which invade into the normal parenchyma and this way they could help the neurosurgeons to more clearly define the borders of the invasive tumour and optimize their surgical approach. Besides selective monitoring of the cathepsins’ activities in vivo by a non-invasive method, the selective CatL probes would prove useful also at evaluating of the predictive tumour response to therapy.
Therefore we predict that the probes developed for CatL would not only be of interest to clinicians working in the field of oncologic surgery, but would also be of interest to the Slovene pharmaceutical industry. Translating novel selective cathepsins probes to clinic, would not only enhance the treatment of cancer patients, but may also enhance the treatment of other types of diseases in Slovenia. The results have namely broader application, as both cathepsins B and L – besides having a role in tumours, also play an important role in processes, such as inflammation (i.e. rheumatoid arthritis and periodontal disease), as well as in bone remodelling and regulation of the cells cycle in postnatal development of the central nervous system.
Last, but no least important remains the fact that this project was providing the ideas and supporting research of five doctoral students, two of which completed with their studies in 2010 and the remaining three being just next to a completion. One of the remaining three doctoral students was supporting and excellent collaboration with the group at CEA Paris, to the point that we succeeded at obtaining continuation of this project for another two years. We hope that at least one of the young scientists trained during this project will continue to do the research in Slovenia and contribute to the scientific excellence of Slovenia.
Most important scientific results
Annual report
2009,
2010,
2011,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2009,
2010,
2011,
final report,
complete report on dLib.si
