Research

Personalised Therapeutics

 ‘What is pharmacogenetics and personalised medicine?’

Group leader

Prof. Dr. Henk-Jan Guchelaar 

Principal investigators

Dr. J.J. Swen, Dr. D.J.A.R. Moes, Dr. Anton T.G. Terwisscha van Scheltinga, Dr. S.Yahya Anvar, Dr. Maarten J. Deenen, Mw. Dr. Jacomijn P. Dijksterhuis

Aim and focus

Drug treatment is the cornerstone of today’s medicine. In this respect, pharmacology is a key driver for the advancement of health care and thus essential for patient’s well-being. However, the outcome of drug treatment is highly variable. Indeed, everyday large numbers of patients receive medications that are, at an individual level, either ineffective or harmful. Therefore, to successfully treat individual patients a personalised therapeutics approach is needed. Genetics has emerged as an important source of variability in drug response and genetic biomarkers are increasingly incorporated in drug and dose selection.

It is our goal to optimize drug treatment of the patient by personalising the dose and drug selection based on a better understanding of the genetic variation that is causal for the inter-patient variability in drug response. We also aim to develop models that include genetic and non-genetic markers that can be readily implemented in daily clinical practice. To achieve these research ambitions we have formed a group of experts that covers the required fields within the area of clinical pharmacology, pharmacogenomics, human genetics, pharmacokinetics, pharmacodynamics, pharmacometrics, bio-informatics 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.

Our research is centred on three main themes: 

  1. Discovery of pharmacogenomic biomarkers in cancer
  2. Implementation of pharmacogenomics in clinical practice
  3. Development of personalised drug treatments

Position in international context

The department is internationally leading in the field of personalised therapeutics, and has a well-recognized expertise and track-record  in the fields of cancer pharmacogenomics and clinical implementation of personalised therapeutics. This is reflected in the large number of invitations to present our scientific progress on conferences (ASCPT, PGRN, ISSX, EACPT, G2MC, KNMP, IMC),  to serve as reviewer (CPT, JCO, CCR, Ann Intern Med) or editorial board member (Pharmacogenomics, Pharmacogenetics Genomics, EJCP), to serve as grant reviewer for international funding organizations (US, Canada, Austria, France, Norway, UK, NL), to serve as members of guideline committees (DPWG, CPIC), and conference programme committees (PGRN, ASCPT, NIH, KNMP). The department has acquired several prestigious international and national grants including a HORIZON2020 grant “Ubiquitous Pharmacogenomics” (coordinator role, €15.000.000), and KWF Alpe d’huez grant “DPD pharmacogenomics” (PI role, €1,200.000).

There is a strong and long standing collaboration with departments and (inter) national institutions involved in Medical Oncology (LUMC, VUMC, Radboud UMC, Erasmus MC, AMC, UMCG, CRO Aviano, University of Chicago), Pharmacogenomics research (Stanford University, St. Jude Children's Research Hospital, the Mayo Clinic Center for Individualized Medicine, Riken Center for Genomic Medicine, Erasmus MC, Radboud UMC, Netherlands Cancer Institute, Karolinska Institute, Royal University Hospital Liverpool), 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 University, Institute for Clinical Pharmacology in Stuttgart). 

Our research group has a very strong position in Europe as is shown by the coordinating role of a large consortium funded by the EU (U-PGx). We are the founding father of the Leiden Network for Personalised Therapeutics, a collaborative network with the mission to coalesce and align academic and patient-oriented research activities in personalised therapeutics. In addition, the development of Personalised Drug Treatments is embedded in the Leiden university research profile Translational Drug Discovery and Development which is co-chaired by our group leader.

Content / highlights / achievements

Discovery studies:

Using both candidate gene and genome-wide approaches, discovery studies for genomic biomarkers for drug response and toxicity were conducted in (intern)national clinical studies in several types of cancer:
  • Colorectal cancer: multiple comparative studies of treatment in mCRC including fluoropyrimidines, irinotecan, EGFR inhibitors (CAIRO); 
  • Breast cancer: prospective clinical study of CYP2D6 and Tamoxifen (CYPTAM); clinical cohort study of aromatase inhibitors (TEAM); 
  • Metastatic renal cell cancer: prospective cohort studies of sunitinib (SUTOX; TOSURE; EUROTARGET)
  • Sarcoma: cohort studies in osteosarcoma including cisplatin; cohort studies in gastro-intestinal-stromal-cell tumors including imatinib and sunitinib

Implementation studies:

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;
In collaboration with the Dutch Pharmacogenetics Working Group, pharmacogenomics-based therapeutic (dose) recommendations for 84 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.Clinical utility of a number of promising pharmacogenomic biomarkers was studied in clinical studies for a variety of gene-drug pairs: A large national prospective randomized clinical trial was finalized on pharmacogenomics (TPMT) based dosing of mercaptopurine in gastroenterology (in collaboration with Radboud MC, Nijmegen; KFT is co-PI).Established a large (n=2,900) project investigating the safety, feasibility and cost-effectiveness of DPYD genotype- and phenotype-directed individualized dosing of fluoropyrimidines in collaboration with the Netherland Cancer Institute (KFT= co-PI).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 (PI).  Received a 15 million Euro Horizon 2020 EU grant as coordinator for the Ubiquitous Pharmacogenomics Project (U-PGx):  ‘Making actionable pharmacogenomic data and effective treatment optimization accessible to every European citizen’.

Future themes

Our pharmacogenomic research will be extended to existing and novel drugs in oncology with a focus on colorectal, renal cell and breast cancer. Whole exome and genome sequencing using the newest technologies (such as PACBIO) will be added to current candidate gene and array based genome wide approaches. Moreover, novel systems pharmacology approaches including population pharmacokinetics, pharmacodynamics, pharmacometrics will be used to expand our understanding of the pharmacology of these drugs and to optimize treatment of the patient by personalizing the dose and drug selection. Indeed, we believe that successful implementation of personalized therapeutics could considerably decrease the incidence of adverse drug reactions. Implementation of pharmacogenomics testing will move from reactive testing for single gene-drug pairs to preemptive panel based. Recently we have expanded our current research-themes with 3 highly innovative explorative research projects: a. phenoconversion in pharmacotherapy; b. computational modelling of growth and clone evolution in heterogeneous tumors; and c. individualised anti-tumor treatment by drug repositioning.

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; dr J. Kroep), Clinical Genetics (Dr. M. Kriek), Human Genetics (Prof. S. van der Maarel) and Medical Statistics (Dr. S. Böhringer) of LUMC.  We have recently started to profile and join the efforts of our institute (LUMC, LACDR, Bio Science Park) in the field of Personalised Therapeutics by forming the Leiden Network for Personalised Therapeutics (LNPT). This network consists of partners having complementary expertise regarding personalised therapeutics from bench to bedside and was founded and is coordinated by our department. Together, these collaborations will add to the development of new clinical and preclinical research methodologies and –technologies in the field of personalised therapeutics.