prof. dr. H.J. (Hiddo) Lambers Heerspink

VIDI project: Systems medicine to unravel therapy response in type 2 diabetes: 

Diabetic nephropathy remains associated with considerable morbidity and mortality despite efforts to improve treatment. The high mortality relates (in part) to clinical routines involving the application of drug trial results to groups of patients without taking the individual characteristics into account. Yet, many drugs have multiple effects that vary between patients. The between-patient heterogeneity in drug response by far exceeds the between-group differences and thus may provide a promising target for exploration and intervention. 

Pharmacogenomics has been applied to explore mechanisms of response variability, thus far with limited success. The complex interplay between genetic make-up and regulation of proteins and enzymes renders pharmacogenomics alone insufficient to capture response variability. I hypothesize that a systems medicine approach integrating genes, proteins, and enzyme activity is a more fruitful approach to link genetic make-up with clinical phenotype to shed light into the black box of factors underlying drug response. 

This project aims to determine the mechanisms and molecular pathways of variability in drug response to develop personalized medicine approaches for patients with diabetic nephropathy.

The project has three parts:

1. Investigate underlying molecular pathways that determine individual differences in drug response by integrating models for diabetic nephropathy disease and drug mechanisms of action. Differences in biomarkers, as proxies of response pathways, are tested in patient samples.
2. Define and validate which patient-specific profiles predict a favorable or poor drug response by profiling the genome, proteome and metabolome. The resulting multi-omic drug response score will be validated in external studies.
3. Identify alternative, already registered drugs for patients unresponsive to current  treatments. A set of drugs specifically addressing the signalling pathways that are active in non-responders is developed.

This project will provide profound understanding of the pathways and mechanisms of drug response in diabetic nephropathy to improve treatment and prognosis of the growing diabetic nephropathy population.