Cancer is a complex disease at the cellular and molecular levels. The presence of a large number of mutations in cancer cells poses a major problem with regard to designing targeted therapeutics. A common strategy to circumvent this problem is to develop cancer drugs that target processes that are upregulated in cancer cells (DNA synthesis, protein degradation, metabolism). Many clinically used anticancer drugs are based on this principle. Our research group is exploring the sensitivities of cancer cells to disruptions of the protein degradation machinery and disruption of energy supplies.
Inhibitors of the ubiquitin-proteasome system - VLX1570
We have identified a new class of inhibitors of the ubiquitin-proteasome system (D'Arcy et al., Nature Medicine, 2011). Our drugs inhibit USP14/UCHL5, two deubiquitinating enzymes (DUBs) in the 19S proteasome. These enzymes normally cleave ubiquitin residues from protein that are destined to be degraded by the proteasome. Drugs that inhibit the activity of USP14/ UCHL5 enzymes will block the function of the proteasome, leading to apoptosis of tumor cells. In collaboration with a biotech company (Vivolux AB, Uppsala, Sweden) we are improving the pharmacological properties of the drugs. We are also working to identify new inhibitors of the ubiquitin-proteasome through screening. We hope that our compounds may be used clinically for the treatment of multiple. Our drug VLX1570 has been approved by the FDA for clinical trials.
Identifying drugs that induce cell death - VLX600
Tumor cells in hypoxic and nutritionally compromised areas in solid tumors are resistant to conventional chemotherapy and radiation therapy. This represents a major problem in clinical oncology. We are attempting to identify drugs that effectively induce cell death of quiescent tumor cells in hypoxic areas. In this project, we use tumor cells cultured in 3-D (multicellular spheroids). One of the substances identified (VLX600) in the screen affects metabolism (Zhang et al., Nature Communications 2014). VLX600 has received FDA approval for clinical trials.
Methods for determination of tumor cell death
We are also interested in developing methods for the determination of tumor cell death after treatment with cytotoxic drugs. Serum biomarkers M30 Apoptosence® and M65® (Kramer et al., Cancer Res 2004) have been developed in collaboration with VLVBio AB (Stockholm, Sweden) and used by the pharmaceutical industry as pharmacodynamic markers in clinical trials.
