Our research program is inherently interdisciplinary and focused on these main research areas:
1. Molecular mechanisms and regulation of human nucleotide excision repair (NER)
NER is the main pathway removing bulky adducts formed by UV irradiation, environmental mutagens and cancer therapeutics from DNA. Our group has made numerous contributions to understanding of the mechanisms of damage recognition, complex assembly and dual incision in NER. Current efforts are aimed at elucidating how protein-protein interaction coordinate the various steps in NER using biochemical, cell biological, structural and single molecule approaches. These efforts will provide detailed mechanistic insights and a guide to how NER may be inhibited for cancer therapy.
2. Trabectedin and lurbinectedin: Elucidating a unique mechanism of drug action for precision oncology
The natural product trabectedin and its derivative lurbinectedin are unique among anticancer drugs in that they are more toxic to cancer cells with high DNA repair activity. We recently uncovered that this is due to an abortive DNA repair reaction in highly transcribed genes of the genome that leads to the formation of cytotoxic DNA breaks. We are now further elucidating the mechanism of trabectedin toxicity, determining where breaks are induced in tumors at a genome wide level and are exploring the potential of trabectedin and lurbinectedin as precision oncology drugs for sarcomas, lung and ovarian cancers.
3. Mechanistic basis of resistance and diagnostic tools for platinum therapy.
Platinum agents (cisplatin, oxaliplatin, carboplatin) are among the most frequently used and successful antitumor drugs, yet there is a surprising lack of knowledge of the mechanisms of how DNA adducts by the platinum drugs are formed and repaired in tumor cells. We have contributed to the understanding of how different platinum adducts are repair by NER and interstrand crosslink repair and have developed tools to monitor the formation and repair of these DNA adducts. Current work is focused on developing new tools and approaches to be able to predict outcomes of platinum therapies.
DNA repair pathways are of fundamental importance for maintenance of genomic integrity and the prevention of carcinogenesis, premature aging and neurodegeneration. Knowledge of DNA repair pathways is also of critical for precision cancer therapy. Despite advances in targeted and immune therapies, most patients still receive cytotoxic DNA damaging drugs. Many tumors exhibit DNA repair defects, which these treatments can exploit. Conversely, high DNA repair activity is associated with (acquired) resistance. The core hypothesis driving our research is that a mechanistic understanding of DNA repair pathways in conjunction with cancer genetics can contribute to improved therapeutic outcomes