Group leaderProf. Dr H.-J. Guchelaar
Aim and focus
The ultimate of aim of the research program is the optimization of drug treatment for patients with cancer or rheumatoid arthritis. More effective and safer drug therapy is achieved by individualization and by use of genetic biomarkers. The focus of the research programme is the discovery of genetic biomarkers that are related to individual drug response. In addition, the programme aims to develop algorithms that include genetic and non-genetic markers that can be readily translated to daily clinical practice. To achieve these research ambitions we have formed a group of experts that covers the required fields within the field of clinical pharmacology: pharmacogenomics, pharmacokinetics, pharmacodynamics, pharmacometrics and bio-analytics. This combination of expertise allows the successful identification of genetic biomarkers for drug response while the clinical environment enables prompt translation to patient care.
Position in international context
There is a strong collaboration with departments and (inter) national institutions involved in Medical Oncology (LUMC, VUMC, Radboud UMC, Erasmus MC, AMC, UMCG), Rheumatology (LUMC, Radboud UMC), Pharmacogenomics research (Stanford University, St. Jude Children's Research Hospital, Shenyang Medical University, Erasmus MC, Radboud UMC, Netherlands Cancer Institute), Human Genetics (Leiden Genome Technology Center, LUMC Medical Statistics, LUMC Human Genetics, LUMC Clinical Genetics, Radboud UMC Human Genetics) and Population Pharmacokinetic/Pharmacodynamic modelling (Leiden Amsterdam Centre for Drug Research, Uppsala Universitet). In addition, Translational Drug Discovery and Development is one of the research profiles of the University of Leiden and is led by the chair of the IPOR programme.
Content / highlights / achievements
- Using both candidate gene and genome-wide approaches, discovery studies for genomic biomarkers for drug response and toxicity were conducted in national colorectal cancer, metastatic renal cell cancer, breast cancer, sarcoma and rheumatology clinical studies.
- Identification and validation of CYP3A5 and ABCB1 as genetic biomarkers for sunitinib toxicity and efficacy in metastatic renal cell cancer in an international collaborative project led by the PIs of IPOR.
- Development of a clinical pharmacogenomic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Currently the model is being validated in a prospective randomized controlled trial.
- Received a 15 million Euro Horizon 2020 EU grant as PI for the project ‘Making actionable pharmacogenomic data and effective treatment optimization accessible to every European citizen’. See www.upgx.eu
- A well-equipped facility for the implementation of clinical Pharmacogenomics has been established. Routine pre-emptive screening programs have been successfully implemented in:
- Oncology: patients receiving capecitabine or 5-fluorouracil tested for DPYD;
- Nephrology: kidney transplant patients receiving tacrolimus tested for CYP3A5;
- Psychiatry: patients with a therapy resistant depression, referred to LUMC for electroconvulsive therapy tested for CYP2D6 and CYP2C19;
- Gastroenterology and Hepatology: patients receiving azathioprine or mercaptopurine tested for TPMT.
- In collaboration with the Dutch Pharmacogenetics Working Group, pharmacogenomics-based therapeutic (dose) recommendations for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, TPMT, DPYD, VKORC1, UGT1A1, HLA-B44, HLA-B*5701, CYP3A5, and factor V Leiden have been developed and integrated with systems for electronic drug prescribing and medication surveillance.
- Initiation of a large pharmacogenomics project in primary care aiming to investigate the opportunities for improving drug treatment in primary care and establish close collaborations with pharmacies in primary care. This present a great opportunity for future research in combination with the master Medical Pharmacy.
- Established a large (n=2,900) project investigating the safety, feasibility and cost-effectiveness of genotype- and phenotype-directed individualized dosing of fluoropyrimidines in collaboration with the Netherland Cancer Institute.
- A large national prospective randomized clinical trial was finalized on pharmacogenomics (TPMT) based dosing of mercaptopurine in gastroenterology (in collaboration with Radboud MC, Nijmegen).
Pharmacogenomic research will be extended to existing and novel drugs in oncology and rheumatology with a focus on colorectal, renal cell and breast cancer and methotrexate and TNF inhibitors respectively. Whole exome and genome sequencing will be added to current candidate gene and array based genome wide approaches. Moreover, novel systems pharmacology approaches including population pharmacokinetics, pharmacodynamics, pharmacometrics and pharmacogenomics will be used to optimize treatment of the patient by personalizing the dose and drug selection.
Cohesion within LUMC
The research program is embedded in the LUMC research profile Cancer Pathogenesis and Therapy. Extensive collaborations exist with the departments of Medical Oncology (Prof. dr. H. Gelderblom) and Rheumatology (Prof. dr. T. Huizinga) of LUMC.