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 a novel inhibitor of the ubiquitin-proteasome system recently identified in our laboratory (D'Arcy, Brnjic et al., Nature Medicine 2011). This molecule inhibits the USP14/UCHL5 deubiquitinating enzymes of the 19S proteasome. 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 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). The mechanisms of action has been solved for some of our screening hits and one compound is close to IND status. This compound induces a bioenergetic catastrophe in quiescent tumor cells in hypoxic areas.
We are also interested in developing methods to determine tumor cell death after treatment with cytotoxic agens. The serum cell death markers M30 Apoptosense ® and M65 ® (Kramer et al., Cancer Res 2004) were developed in collaboration with Peviva AB (Bromma, Sweden) and are used by the pharma industry as efficacy markers in clinical trials. In a collaboration with other KI and KTH scientists we are also developing imaging methods to determine cell tumor death and tumor load in vivo.
An additional research line led by Angelo De Milito focuses on the implications and role of pH alterations in tumor progression and therapy. Because of the high glycolytic flux, accelerated metabolism and aberrant perfusion tumor tissues tend to accumulate metabolic acids (lactic acid, protons). Acidification of tumor tissues has been recognised as a fundamental mechanism for malignant progression and therapy resistance and the group aims at 1) identifying anti-cancer compounds selectively active on low pH-adapted cancer cells and 2) characterising how autophagy sustain cellular adaptation to acidic conditions (Marino ML, et al). The projects are granted by the Worldwide Cancer Research and the Swedish Cancer Society.
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
Stig Linder, Professor
Maria Hägg Olofsson, PhD
Padraig D´Arcy, PhD
Angelo De Milito, PhD, Associate Professor
Magdalena Mazurkiewicz, PhD student
Xiaonan Zhang, PhD
Paola Pellegrini, PhD student
Ellin-Kristina Hillert, PhD student