A main focus of our research group is to identify new inhibitors of the ubiquitin-proteasome system (D'Arcy, Brnjic et al., Nature Medicine 2011; Mofers et al., Eur J Pharmacol. 2020). The molecules b-AP15/VLX1570 inhibit two deubiquitinating enzymes (USP14/UCHL5) in the 19S proteasome. We and other groups have shown that these substances exhibit significant antitumor activity in various tumor models. By using combinations of different methods, we aim to understand the molecular mechanisms of action of our molecules (Gubat et al., Front Oncol. 2022). We hope that drugs can be developed that can be used to treat multiple myeloma resistant to the proteasome inhibitor Velcade®. Through the use of CRISPR loss-of-function screens, we aim to understand the importance of different deubiquitinases for the viability of cancer cells with different genetic backgrounds.
Using tumor cells grown in 3-D culture (multicellular spheroids), we have shown mitochondrial metabolism is essential for cells growing in starved and hypoxic regions (Zhang et al., Nature Communications 2014). Our results show that tumor cells in such regions have limited capacity for metabolic plasticity and we are working to identify drugs that can be used for the treatment of solid tumors, mainly advanced ovarian cancer (Zhang et al., Int J Mol Sci. 2021).