Stig Linder's Group
Identification of drugs for treatment of solid tumors. Our group works in the field of drug discovery and cancer pharmacology. We utilize advanced screening assays to search for novel cancer drug candidates.
A major focus of our laboratory is to understand the mechanism of action of novel inhibitors of the ubiquitin-proteasome system identified in our laboratory (D'Arcy, Brnjic et al., Nature Medicine 2011). These molecules inhibit the USP14/UCHL5 deubiquitinating enzymes of the 19S proteasome. We and other groups have demonstrated that these compounds show considerable anti-tumor activity is various tumor models. Lead-optimization in order to develop a drug for clinical use is ongoing. This work is performed in collaboration with Vivolux AB, Uppsala and with Uppsala University. We hope that a drug can be developed that can be used to treat multiple myeloma resistant to the proteasome inhibitor Velcade ®.
We are interested in the understanding the biological role of proteasome deubiquitinases and are working with conditional knock-out cell lines and mouse models.
We have developed methods to screen for compounds that are effective in inducing cell death of tumor cells grown in 3-D culture (multicellular spheroids). The long-term goal is to identify drugs which can be used for treatment of solid tumors. We find that compounds effective in 3-D culture generally have hydrophobic properties (Fayad et al., Chem Biol Drug Des. 2011). We have shown that compounds that show activity in 3-D models inhibit mitochondrial metabolism and have hypothesized that tumor cells in starved and hypoxic regions have limited capacity for metabolic plasticity (Zhang et al., Nature Communications 2014). We are currently testing this hypothesis for the treatment of advanced ovarian cancer.
Mechanistic studies of a novel inhibitor of the ubiquitin-proteasome system
Inhibition of 19S proteasome deubiquitinases as a promising strategy in cancer therapy
Tumor acidosis in malignant progression and therapy
Development of therapeutic strategies for quiescent tumor cell populations
Different approaches to develop radio- and chemotherapy for treatment of human cancer
Studies of overcoming acquired resistance: molecular mechanisms and development of novel drugs
Identification and characterization of a proteasome deubiquitinase inhibitor
Using a 3-d model system to screen for drugs effective on solid tumors
On the role of different signal transduction pathways in induction of apoptosis by anticancer drugs
Maria Hägg Olofsson
Translational studies of drug-induced tumor cell death
Characterization of the mechanisms of action of anticancer agents in vitro and monitoring their effects in vivo
Analyses of the expression and function of the aspartic protease napsin
On the role of SAP kinase pathways in cellular responses to cancer treatment
Elucidation of pro-apoptotic signaling induced by cisplatin
The prognostic significance of uPA, uPAR and the cytokine IL-1-alpha in urinary bladder cancer