Merle van Gelder

Research

Anthracyclines are a class of chemotherapeutics that are extensively used in the treatment of various cancers ever since their initial discovery in the 1960s. While anthracycline drugs are highly effective in the treatment of both hematological malignancies and solid tumors, their clinical application is limited by side effects and hampered by drug resistance. It has long been appreciated that doxorubicin and its analogues daunorubicin, epirubicin and idarubicin cause DNA double-strand breaks following poisoning of topoisomerase II. More recently, our lab has shown that some anthracycline variants induce chromatin damage which is achieved through eviction of histones from select sites in the genome. Systematic research on the activities of novel anthracycline analogues has revealed that variants which induce chromatin damage without causing DNA double-strand breaks abstain from causing cardiotoxicity and therapy-related tumors but retain potent anti-cancer activity. Drug resistance is often a result of the upregulation of transporters by tumor cells, of which ABCB1 (MDR1) is the most well described. The expression of this exporter is often treatment induced, and anthracyclines that are currently used in the clinic are a known substrate for ABCB1.

We have synthesized many novel anthracycline variants by altering the chemical  structure, to obtain drugs with limited toxic effects and lower affinity for the ABCB1 transporter. These structure-activity studies within the anthracyclines family offer opportunities towards the development of effective analogues with limited adverse effects. Ultimately, these variants would then be better tolerated by patients and could be used for the treatment of doxorubicin resistant tumors.

Curriculum Vitae

I completed my Masters in Biomedical Sciences at the University of Amsterdam with a focus on experimental internal medicine. In 2020 I joined the Neefjes lab as a PhD student to study the working mechanism of anthracyclines.