Epitelijska celična adhezijska molekula (EpCAM) - tarča tumorske terapije: struktura, proteolitično procesiranje in interakcija z drugimi proteini (Slovene)

The goal of this project is to generate functional and structural data that will allow the development of a novel EpCAM-based approach for cancer therapy and prevention. Epithelial cell adhesion molecule (EpCAM) is up-regulated in a variety of carcinomas and has recently been identified as a cancer stem cell marker (CD 326) with a direct impact on the cell cycle. This qualifies EpCAM as a promising target for design of drugs used to treat cancer patients. So far, several immunotherapies have been developed, yet with limited success in clinical trials. We believe that the therapeutic effect can be prominently improved by combining immunotherapy with agents that will debulk the tumor tissue and thereby improve the accessibility of cancer stem cells to the immune system. Our contribution in this respect will be oriented at studying EpCAM at the molecular level by revealing the mechanisms of EpCAM dimerization/oligomerization and its interaction with the actin cytoskeleton via ?-actinin on the structural level. This will open completely new perspectives for the design of novel therapeutic agents (inhibitors) that will interfere with binding sites to prevent the EpCAM signaling pathways critical for tumor development. Furthermore we will expand our knowledge of the EpCAM interactome by searching for novel binding partners that bind to different modules of EpCAM. We will also investigate the importance of proteolytic processing of EpCAM for tumor progression. Results obtained at the molecular level will be validated for their biological effects using different cultured tumor cells. Our approach is highly interdisciplinary and knowledge of the structural-functional characteristics of EpCAM interactome represents an innovative approach in this highly competitive area.

Besides its direct impact on the general knowledge of the science, the project itself will also have an indirect impact on Slovene society. It will sprout new collaborations with some of the leading scientists in the area of cancer research. In the same time the results of our work will also be a basis for further novel collaborations with Slovenian research groups specializing in the production of antibodies or small-molecule compounds targeting EpCAM as well as collaboration with clinical researchers. All together will greatly contribute to the development of the Chair of Biochemistry at the UL FCCT as a competent and independent research group. This will in turn be reflected in the quality of education passed on to the students of our faculty, in the sense of both being able to present them with first-hand quality research as well as offer the students an opportunity to become involved in high-quality research in the future.