The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Clinical Pharmacy and Toxicology.
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.
Aim and focus
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: Discovery of pharmacogenomic biomarkers in cancer, Implementation of pharmacogenomics in clinical practice, and Development of personalised drug treatments. In addition, recently we have expanded our current research-themes with 3 highly innovative explorative research projects (see 5. Future Themes).
Theme 1: Discovery of pharmacogenomic biomarkers in cancer
The aim of this theme is to discover pharmacogenomic biomarkers that are predictive for drug efficacy and toxicity in cancer treatment. Especially in cancer treatment biomarkers for predicting drug efficacy and toxicity are highly needed. Cancer patients still have a poor prognosis and a limited life expectancy. Since the efficacy of anti-cancer drug treatment can generally only be assessed after several months of treatment, early prediction of response is essential and holds the promise to optimize treatment outcome. In addition to a sometimes limited activity, many applied anti-cancer treatments are highly toxic and can cause high rates of morbidity and even mortality.
Within the field of solid tumors we focus on discovery of pharmacogenomics biomarkers for treatment of breast cancer, colorectal cancer, sarcoma, and renal cell cancer. Breast and colorectal cancer are amongst the most frequently occurring cancers in the western world and for both drug-treatment is an important part of the treatment strategy. In recent years significant progress has been made in the targeted treatment of (metastatic) renal cell cancer and multiple targeted treatments are available and pharmacogenomics biomarkers may be utilized to select the best therapy for a particular patient.
To discover pharmacogenomics biomarkers, large scale association studies in well phenotyped patient cohorts are executed. Multiple approaches are applied ranging from drug mechanism and pathophysiologically informed methods to hypothesis free approaches. Corresponding techniques include candidate-gene genotyping, gene-panel and pathway genotyping, genome wide array based genotyping and large scale sequencing techniques. In addition to association studies, we strive continuously to improve methodologies by taking advantage of novel techniques to profile and characterize individuals based on their genome and transcriptome at single-molecule resolution. By using a multi-layer omics approach, we study the genetic factors that alter mRNA processing that result in functional divergence of pharmacogenes.
In this way we not merely aim for discoveries of new pharmacogenomic biomarkers but also aim to advance the scientific methodologies in the field of personalised therapeutics.
Theme 2: Implementation of pharmacogenomics in clinical practice
In recent years a number of randomized clinical trials have provided evidence for the clinical validity of pharmacogenomic tests to guide both drug and dose selection. The availability of pharmacogenomic guidelines by the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium have facilitated the implementation of personalized therapeutics in routine patient care. Still, hurdles for implementation exist including physician and pharmacist awareness and knowledge, and development of tools to implement pharmacogenomics results into the workflow of physicians and pharmacists. This theme aims to translate promising pharmacogenomic biomarkers emerging from discovery studies (as described in theme 1) to clinical practice.
Until now, implementation activities have focused on implementing mainly reactive pharmacogenomic testing for single gene-drug pairs. Technological developments are a major driver to transfer to preemptive panel based pharmacogenomic testing. In addition, recent studies have demonstrated that genetic variation is common. Approximately95% of the population carries at least one actionable genotype when tested for a panel of 5-10 pharmacogenes. However, the clinical utility of this panel based preemptive approach has not been shown and is the focus of this research theme.
Theme 3: Development of Personalised Drug Treatments
The rationale for the Leiden Personalized Cancer Immunotherapy approach and production of neoantigen directed anti-tumor vaccines is based on the recent discovery of the key role of mutanome-specific T cells, recognizing “non-self” neo-antigens that arise from mutations in the tumor genome. The in-depth analyses of anti-tumor T cell responses by rapid sequencing technologies have consistently demonstrated the relationship between mutanome-specific T cell immunity and clinical regressions in a wide range of different tumors. In this research theme, these recent insights in immuno-oncology will be translated towards improved clinical benefit by a new therapeutic personalised intervention. Leiden has the full expertise and infrastructure available to develop, synthesize and provide mutanome vaccines to individual cancer patients.
In the Molecule2Man project, we will investigate mutanome-specific T cell responses and initiate the first mutanome-based therapeutic vaccination trial in colorectal cancer (CRC) patients. Moreover, the chemical design and pharmaceutical formulation of mutanome-based vaccines will be improved to provide the most potent and technically feasible mutanome vaccine.
The drug development pipeline includes the chemical design and development of improved TLR-L conjugate vaccines (LIC, with LACDR / IHB / KFT), investigation on the mechanism and optimization of liposomal vaccine formulations (LACDR, with IHB / KFT / 2-BBB), an observational study on mutanome responses in colorectal cancer patients (Oncology, with Pathology), identification of targetable mutanome peptides (Pathology, with Oncology), establishment of a process for high throughput GMP manufacturing of mutanome peptides (KFT), transfer of the selected formulation to GMP and non-clinical GLP toxicity (KFT) and execution of a personalized cancer immunotherapy clinical trial in CRC patients (Oncology, with Pathology / IHB / KFT / ISA).
The role of KFT in this multidisciplinary and multidepartmental mutanome project is focused on the GMP synthesis and production and formulation of the peptide vaccines and supervision of the pharmaceutical development process.
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 (https://www.lumc.nl/org/lnpt/). 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 (http://www.onderzoeksgebieden.leidenuniv.nl/en/effective-drug-development/).
Content / highlights / achievements
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
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’. See www.upgx.eu.
- 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: phenoconversion; computational modelling of growth and clone evolution in heterogeneous tumors; and individualised anti-tumor treatment by drug repositioning.
- Phenoconversion: The search for personalized therapeutics relies on genetic factors (genotypes) that define the functional capacity of an individual to metabolize drugs (phenotype). However, factors such as disease-state, inflammatory cytokines, and co-medication may modify the metabolic function in ways unexplained by the genetic background due to a phenomenon called phenoconversion. In this project, we explore the molecular mechanisms of phenoconversion and will utilize this phenotypical variation to better predict drug response in individuals.
- Computational modelling of growth and clone evolution in heterogeneous tumors: Increasingly, in cancer treatment drug choice is based on the presence of specific somatic mutations or protein expression in the tumor. However, due to tumor heterogeneity and clonal evolution this process is highly dynamic and therefore the most appropriate targeted drug may change over time. In this project, we will develop pharmacometric models which describe tumor growth kinetics and clonal evolution, drug sensitivity and pharmacokinetics and combine these characteristics into a systems pharmacology model which enable us to design the most accurate targeted treatment for an individual patient with a dynamic disease.
- Individualised anti-tumor treatment by drug repositioning: In the era of increasing drug costs ‘drug repositioning’ is a hot topic: existing drugs are explored for novel indications. As such, disease specific DNA expression profiles can be utilized to characterize a disease or even more specifically characterize a tumor in the individual patient. Drugs are known to change DNA expression and databases with drug specific effects on DNA expression are publicly available. It is hypothesized that drugs that are able to reverse the aberrant DNA expression in diseased patients are potential drug candidates for treatment of the disease. Indeed, data have shown that that drugs developed and used for a specific indication have unforeseen pharmacological effects in other diseases. In the project, we will explore drug repositioning for cancer treatment. Available public databases with DNA expression profiles of diseases and licensed drugs will be utilized for candidate discovery, algorithms will be further developed and improved and (pre)clinical studies will be designed for proof of concept.
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; https://www.lumc.nl/org/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.