Research
Research
Research Focus
Nuclear receptors are drug targets of no less than 16% of small-molecule drugs. In this respect, the glucocorticoid receptor (GR) is a well-known nuclear receptor family member and drug target. Synthetic drugs that activate the GR, i.e. corticosteroids, are frequently used in the clinic to treat or manage immune and inflammatory diseases and (hematological) cancers. Corticosteroids are very effective but prolonged treatment is hampered by the emergence of resistance and many side effects including increased blood sugar levels, osteoporosis, psychological disturbances and body weight gain, to name but a few. Side effects may arise because corticosteroids are too often used with a “one-size-fits-all” rationale in the clinic, while GR signaling is far more complex than previously recognized. This is illustrated by the existence of multiple GR conformations, which may attract specific coregulators, ultimately likely giving rise to different therapeutic and side effect profiles.
Therefore, in our lab, we develop novel drug discovery platforms that enable capturing this complexity in GR signaling, which ultimately may lead to the identification of safer and disease-tailored selective GR-targeting drugs. We also strive to elucidate the mechanisms that dictate the onset of corticosteroid resistance by engineering relevant cell models. We then use this knowledge to propose drug combination strategies that may re-sensitize cells to corticosteroid therapy in a timely manner.
Our team played a pioneering role in the booming field of nuclear receptor crosstalk. GR and other nuclear receptors, such as MR, PPAR and ERR, were recently recognized to also interact functionally and differently depending on the disease context. Our goal is to decipher these crosstalk mechanisms and to exploit the resulting knowledge to develop innovative nuclear receptor-targeting strategies with enhanced therapeutic benefit. For instance, we discovered that many nuclear receptors form (unconventional) heterodimers and thus may well represent brand-new drug targets. This opens up opportunities for developing novel ligands that simultaneously target both nuclear receptor partners and give rise to fewer side effects. The fields of application of our strategies range from chronic inflammatory and metabolic disorders to (drug-repurposing) strategies in (hematological) cancers.