Projects / Programmes
Use of cathepsin B and X inhibitors for the improvement of antitumor therapy
| Code |
Science |
Field |
Subfield |
| 3.04.00 |
Medical sciences |
Oncology |
|
| Code |
Science |
Field |
| T490 |
Technological sciences |
Biotechnology |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
Cathepsins, Cancer, Cancer Stem Cells, Inhibitors, Tumor resistance, Antitumor therapy, Chemotherapy, Invasion, Migration
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
36440 |
PhD Ana Mitrović |
Pharmacy |
Head |
2018 - 2020 |
112 |
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0106 |
Jožef Stefan Institute |
Ljubljana |
5051606000 |
90,742 |
Abstract
The effectiveness of cancer treatment is limited by development of resistance and cancer recurrence. In heterogeneous tumors most of the currently available therapeutic approaches mainly affect rapidly dividing, differentiated cells while a minor population of cancer stem cells (CSCs) survives, enabling tumor renewal. Therefore, to overcome limitations of conventional antitumor therapy and to achieve prolonged disease free period novel therapeutic approaches being effective also against CSC are needed.
Cathepsins B and X could serve as molecular targets able to enhance CSCs directed therapy. In cancer, these redundant lysosmal cysteine carboxypeptidases are associated with less differentiated cell phenotype and as shown recently, they are able to switch tumor cell phenotype between epithelial and mesenchymal. Furthermore, they are present in higher levels also in CSCs. Increased activity of cathepsins B and X can be selectively regulated at multiple levels, including specific small molecular inhibitors, developed recently by our group.
We hypothesize that cathepsin B and X inhibitors may increase differentiation of CSC and improve the effectiveness of the conventional chemotherapy. In the present project we will combine selective reversible inhibitors of cathepsins B and X with conventional chemotherapy, directed to differentiated cancer cells. We will evaluate the impact of combinations on differentiation of CSCs, and test the overall effect on cell death and on functional properties of tumor cells in vitro on models of cell migration and invasion and in vivo on models of tumor growth and metastasis. Taken together, our proposed project represents innovative approach in overcoming limitations of current antitumor therapy with aim to avoid therapy resistance and cancer recurrence.
Significance for science
Globally cancer is the second leading cause of death and its incidence is highly increasing due to prolonged lifetime. Cancer today therefore represents major healthcare as well as social and economic issue in the developed countries. Regardless rapid development to improve the effectiveness of the therapy, cancer recurrence and metastasis are still the major issues decreasing the survival of cancer patients. Thus, novel approaches are urgently needed to overcome current limitations. In the heterogeneous tumor cell population CSCs, a subpopulation of tumor cells that is the most resistant for conventional chemotherapy, are considered as the main driving force towards tumor invasion and recurrence. In this project we specifically focus on development of the new approaches to achieve therapeutic effect against CSC. New potent and selective peptidase inhibitors, specifically directed against upregulated peptidases, would be appropriate supplement to the chemotherapy in achieving CSCs directed therapeutic response. They may stimulate CSCs to differentiate and be more acceptable for conventional antitumor therapy. Moreover, addition of peptidase inhibitors to conventional chemotherapy can decrease side effects, since lower doses of chemotherapeutic could be used for the same therapeutic effect. Besides overcoming resistance to antitumor therapy, results of the proposed project are expected to significantly expand knowledge regarding the role of cysteine cathepsins in CSCs and mechanisms involved in resistance against chemotherapy. The results of this project could be important for patients since better effectiveness of antitumor therapy may lead to prolonged disease free period and complete healing of the patients with a significant impact on quality of life, accompanied also with a positive economic impact on health system. Additionally, the novel results could be of potential interest for pharmaceutical industry for development of new antitumor drugs and could also encourage entry of novel peptidase inhibitors into clinical trials as well as enhance development of novel therapeutic regimes for cancer treatment.
Significance for the country
Globally cancer is the second leading cause of death and its incidence is highly increasing due to prolonged lifetime. Cancer today therefore represents major healthcare as well as social and economic issue in the developed countries. Regardless rapid development to improve the effectiveness of the therapy, cancer recurrence and metastasis are still the major issues decreasing the survival of cancer patients. Thus, novel approaches are urgently needed to overcome current limitations. In the heterogeneous tumor cell population CSCs, a subpopulation of tumor cells that is the most resistant for conventional chemotherapy, are considered as the main driving force towards tumor invasion and recurrence. In this project we specifically focus on development of the new approaches to achieve therapeutic effect against CSC. New potent and selective peptidase inhibitors, specifically directed against upregulated peptidases, would be appropriate supplement to the chemotherapy in achieving CSCs directed therapeutic response. They may stimulate CSCs to differentiate and be more acceptable for conventional antitumor therapy. Moreover, addition of peptidase inhibitors to conventional chemotherapy can decrease side effects, since lower doses of chemotherapeutic could be used for the same therapeutic effect. Besides overcoming resistance to antitumor therapy, results of the proposed project are expected to significantly expand knowledge regarding the role of cysteine cathepsins in CSCs and mechanisms involved in resistance against chemotherapy. The results of this project could be important for patients since better effectiveness of antitumor therapy may lead to prolonged disease free period and complete healing of the patients with a significant impact on quality of life, accompanied also with a positive economic impact on health system. Additionally, the novel results could be of potential interest for pharmaceutical industry for development of new antitumor drugs and could also encourage entry of novel peptidase inhibitors into clinical trials as well as enhance development of novel therapeutic regimes for cancer treatment.
Most important scientific results
Final report
Most important socioeconomically and culturally relevant results
Final report
