IMTM

Carbonic anhydrase IX (CA IX) is highly overexpressed in different solid tumors. It is a transmembrane isoform of carbonic anhydrase with an extracellular-facing catalytic site and therefore is well positioned to act in the control of tumor pH. Function of CA IX can be inhibited by CA IX-selective sulphonamides. Inhibition its function perturbs in vitro survival under hypoxia conditions. The aim of this study is to evaluate the effect of new carboranes with functional sulfonamide residues on CA IX function. Carboranes, icosahedral clusters containing boron, carbon and hydrogen replace various hydrophobic structures in biologically active molecules. The most interesting drugs were chosen based on enzymatic assay. To characterize their CA IX inhibition mode in cellular level, several cell biology methods were used. Drug cytotoxicity and consequently extracellular pH of carboranes treated cell lines under hypoxia conditions was evaluated. Data shows reversed hypoxia-induced decline of extracellular pH in treated HT-29 and 4T1 cell lines. Moreover, we set up a new method of Raman spectroscopy locating carboranes distribution in cells. To extend this study, pharmacokinetics and pharmacology profile describe ADME methods and experiments on animal model. The results shows the ability of these compounds inhibit CA IX in enzymatic level and cellular level. Thus, novel carboranes with functional sulfonamide residues indicate new selective CA IX inhibitors as potential anticancer drugs.

The project focuses mainly on identification, verification, and implementation of biomarkers for prognostic and predictive purposes in colorectal, lung, thyroid cancer and melanoma with utilization of instrumental capacities of Institute of Molecular and Translational Medicine. These biomarkers can be applied in situations directly linked to patient care, drug development, and research. The ultimate goal is to strengthen the knowledge base in identification and validation of biomarkers on the molecular level.

Glycosylation of cellular proteins post-translation has been reported to be an indicator of altered cellular physiology. The larger goal of the work is to identify marker glycoproteins for the different gastrointestinal cancers using the HCT116 mouse xenograft model system.