Research @ De Bosscher group

Translational Nuclear Receptor Research

Mission statement
Translational: Basic scientific research with a focus on novel anti-inflammatory therapies (to circumvent side effects), novel anti-cancer treatments (to overcome resistance and side effects) and the development of advanced GR-tailored drug screening platforms
Nuclear Receptor: Focus on GR, MR, PPAR and ERR as individual drug targets and crosstalk mechanisms. These NRs (signaling and transcriptional mechanisms) are studied in-depth on a biomolecular level.
Research: Combining dry and wet lab experiments to validate fundamental insights in biologically/clinically relevant settings. Expertise with cell-based anti-inflammatory drug screening platforms.

Research_DeBosscher

Currently, corticosteroids in the clinic are too often used with a “one-size-fits-all” rationale for the treatment/management of inflammatory diseases, metabolic disorders and cancer. Glucocorticoid receptor (GR) regulation and responses are far more complex than previously recognized. GR is not a “one-size-fits-all” type of target, but requires a tailored approach when it comes to drug discovery to meet the correct insight that GR is a receptor demonstrating a high degree of plasticity. Multiple GR conformations must exist, likely resulting in different anti-inflammatory (AI) profiles. Trying to achieve a selective GR-mediated activation of particular AI profiles may offer the potential for the development of safer and disease-tailored GR-targeting medicines. Figure 1: Desmet and De Bosscher, J Clin Invest. 2017;127(4):1136-1145)

A better selectivity may be reached either by GR ligand screenings/rational drug design (classic approach) or by exploiting opportunities that arise from the recent recognition that several NRs interact physically and functionally with different members of the NR family (our original approach).

We hypothesize that a re-wiring of nuclear receptor cross-talk mechanisms towards unconventional, but favorable, nuclear receptor heterodimers may influence gene expression patterns such that enhanced therapeutic benefit may be within reach. The latter phenomena allow for the development of novel ligands with affinity for, and (anta)agonism for, both NR partners. The fields of application of our strategies range from chronic inflammatory and metabolic disorders to drug repurposing strategies in cancer.