Molecular Pathology: Jan Schellens
Jan Schellens, M.D. professorGroupleader
- +31 20 512 2446
Research interest: Personalized Cancer Treatment
Phase I Clinical Trials with targeted
The development of anti-cancer therapies has undergone a radical change over the last decades: from conventional cytotoxic drugs that don't discriminate between normal and tumor cells, to so-called targeted therapies which inhibit a specific target within a tumor cell.
The targets are mostly comprised of receptors or tyrosine kinases that have become aberrant in tumor cells, which can cause uncontrolled cellular signaling and growth.
Within our research group, we perform many phase I studies with inhibitors of these specific targets, both in the form of small-molecule inhibitors as well as monoclonal antibodies. Since this is the first time these anti-cancer therapies are administered to humans, the main goal of these studies is to characterize the safety and pharmacokinetic profile and to determine a recommended dose for further clinical development.
In recent years, it has become apparent that these targeted therapies have relatively modest anti-tumor activity, which is mostly due to the tumor cells developing resistance through mutations in parallel cellular signaling pathways. Thus, development of these compounds has steered more towards combining these compounds.
In support of clinical trials, our research group also focuses heavily on the development of pharmacodynamic assays, which could help us in diagnosis, but also in determining which patients benefit more from treatment.
These assays include the quantification of poly(ADP-ribose) polymerase (PARP) inhibition in peripheral blood mononuclear cells (PBMCs), which is currently validated in phase I clinical trials with the PARP-inhibitor olaparib, and circulating endothelial cells (CECs) in plasma.
Furthermore, we are in the process of validating a new assay to determine circulating tumor cells (CTCs) both in blood samples and in cerebrospinal fluid. With this assay, we could possibly detect signs of disease progression at an earlier stage.
Lastly, we are involved in optimizing assays for the determination of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) activity. These enzymes plays an important part in the metabolism and activity of fluoropyrimidines. Patients with decreased metabolism are at risk of developing serious toxicities and thus determining the DPD activity before starting treatment could warrant a dose adjustment.
In collaboration with our pharmacy department, our research groups conducts trials to test the safety and pharmacokinetics new oral formulations of intravenous anti-cancer drugs, such as docetaxel and paclitaxel.
Furthermore, to optimize treatment of tyrosine kinase inhibitors, we aim to develop and/or optimize therapeutic drug monitoring (TDM) for both new and existing anti-cancer treatments.
Additionally, the collaboration with the pharmacy also allows us to explore other types of pharmacological research, such as mass balance studies, measurements of intracellular metabolites of anti-cancer drugs and pharmacokinetic and pharmacodynamics modeling and simulation.
- Judith BootResearch Assistant
- Emilie van Brummelen, MScPh.D. Student
- Mark van Bussel, MScPh.D. Student
- Robin van Geel, MScPh.D. Student
- Jill Geenen, MSc, M.D.Ph.D. Student
- Linda Henricks, MScPh.D. Student
- Bart Jacobs, MScPh.D. Student
- Pia van der LaanResearch Assistant
- Ruud van der NollPh.D. Student
- Dick Pluim, BScTechnician
- Willeke Ros, MScPh.D. Student
- Vincent de Weger, MSc M.D.Ph.D. Student
My name is Judith Boot and I'm 26 years old. I started working
in May 2015 as research assistant for the Schellens group
supporting the other PhDs, among other things helping them with
data entery. At this moment I'm working on the M13DAP and the
M14LTK. This is not my first time working at the NKI. Earlier I
worked as datamanager at the trialbureau and in 2013 I briefly also
worked as research assistant for the Schellens group. I did this
work during the time I had breaks of studying Medicine.
In April 2015 I finished medical school at the VU university. I'm looking for a job as clinical physician in Internal medicine. Until I find this job I'll be working at the NKI.
Emilie van Brummelen, MSc
I am doing my PhD in Prof. Jan Schellens' research group on the
division of Molecular Pathology. In my research I focus on phase
I/II clinical studies. I finished the Master in Pharmacy and the
Honours Programme of Pharmaceutical Sciences at Utrecht University
in the end of 2013. During my studies, I did an internship at Bayer
Pharma in Berlin, and at several pharmacies and hospitals in the
Netherlands. Next to that I worked on a research project on the
development of polyomavirus-derived virus-like particles by
directed evolution at the group of Pharmaceutics at Utrecht
University. Also I did research on the effect of broccoli on the
CYP2D6 phenotype in vitro and in vivo.
During my studies it became more and more clear that clinical research is one of my main interests. That brought me here to work on clinical trials for my PhD, to learn about all aspects of clinical research.
Mark van Bussel, MSc
In 2013 I finished my Master in Pharmacy at Utrecht University. In my master research project I studied the pleiotropic effects of statins and ACE-inhibitors in patients with COPD at The University of Alabama at Birmingham, United States. Thereafter, I worked as a pharmacist in a hospital pharmacy. I work as a Ph.D. student in the group of Prof. Dr. Jan Schellens. My projects focus on phase I/II clinical studies.
Robin van Geel, MSc
As a PhD-student I work on early phase clinical studies focusing on targeted anti-cancer agents and combination strategies. One of my projects involves a phase I/II study combining a BRAF inhibitor with an EGFR inhibitor in patients with BRAF mutated metastatic colorectal cancer. This experimental therapy is based on preclinical data that suggested that both BRAF and EGFR should be targeted to effectively inhibit growth of BRAF mutated colorectal cancers. Preliminary results suggest that this treatment is very effective in this selected group of patients, with tumor responses in a substantial part of the patients at the expense of very limited adverse events.
Jill Geenen, MSc, M.D.
In 2012 I finished medical school at the University of Amsterdam
cum laude. During medical school I did an internship oncology at
the NKI. The first year after graduating I worked as a resident of
internal medicine in Flevo Hospital. Hereafter I entered a resident
training program to become an internist. The past eighteen months I
worked as a resident in internal medicine.
Due to increasing interest in research I decided to interrupt my residency. Currently I work as a PhD student in the Jan Schellens group jointly with the group of Sabine Linn. During my PhD studies I will focus on phase I/II clinical trials. My main focus will be the REVIVAL study of carboplatin-olaparib in BRCAm breast cancer patients.
Linda Henricks, MSc
As a PhD student in the group of Prof. Jan Schellens the focus of my research is on the safety, feasibility and cost-effectiveness of genotype- and phenotype-directed individualized dosing of fluoropyrimidines. In August 2014 I finished my master in Pharmacy at the Utrecht University cum laude. During my master I did an internship at the University of California in San Francisco where I studied the Ras pathway in colorectal cancer.
Bart Jacobs, MSc
After finishing my Masters in Pharmacy in the end of 2011 (Utrecht University) I started working as a PhD student in the group of Prof. dr. J.H.M. Schellens. My research project is focused on the development and clinical testing of new oral fluoropyrimidine drugs in order to explore implications for chronotherapy. This research is supported by bioanalytical projects in order to develop and validate assays which can be applied in the clinical studies. In addition, to gain more insight in the pharmacology of oral fluoropyrimidines, I'm currently working on the development of a population based pharmacokinetic model for capecitabine.
Pia van der Laan
My name is Pia van der Laan, I am a medical student at the VU University and working as research assistant at the Jan Schellens group. After I finished my bachelor in medical biology, I started a research master in oncology. During this master, I performed an internship at the Jan Schellens group working on fluoropyrimidine safety. After this internship I returned a few times to help with data entry of clinical trials during my holidays. Last september I started as medical student with a pre-master program to start my master in medicine next year. Besides my studies I work on the M14DPD study, in which patients treated with fluoropyrimidines are dosed based on different geno- and phenotypes to improve patient safety.
Ruud van der Noll
I finished my Master in Pharmacy at the University of Utrecht in
2009. After working as a pharmacist for a little while, I decided
to take on a more challenging position and started working as a PhD
student for the Schellens group at the NKI.
My research mainly focuses on several phase I studies in which new compounds or new combinations of existing drugs are given to patients for the first time. In these studies we try to establish what the toxicities are and what the recommended dose is for future studies, but also investigate whether there is evidence of preliminary anti-tumor activity.
Dick Pluim, BSc
I am involved as an independent researcher in the development and validation of non-invasive predictive and pharmacodynamic biomarker assays for monitoring the effect of molecular targeted anticancer agents. These assays can be used to predict if a patient will benefit from a particular treatment. This work includes: 1. enzymatic activity assays for dihydropyrimidine dehydrogenase, thymidine synthase, and polyADPribose polymerase. 2. assays for the enumeration of circulating epithelial and melanoma tumor cells.
Willeke Ros, MSc
My name is Willeke Ros and I am a PhD student at Jan Schellens group. I have completed my bachelor in Biology and my master in Biomedical Sciences at Leiden University. During my studies I have performed various internships focusing mostly on fundamental research questions. However, during my last internship at the University of Wisconsin-Madison, I did research which was part of clinical trials. I enjoyed the translational nature of the research and decided I wanted to continue doing clinical research. During my PhD studies I will focus on phase I/II clinical trials related to immunotherapy.
Vincent de Weger, MSc M.D.
In 2011 I finished medical school at the VU university. I also enrolled in the Honors program performing my own scientific project for which I was awarded the honors degree in Medicine. After medical school I have worked as a resident at Spaarne Hospital.
Currently I work as a PhD student. My work focuses on fase I and II drug development studies, both MODRA and sponsor initiated.
Key publications View All Publications
Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis
(2015) J Clin Oncol. Nov 16. pii: JCO.2015.63.1325. [Epub ahead of print]
Deenen MJ, Meulendijks D, Cats A, Sechterberger MK, Severens JL, Boot H, Smits PH, Rosing H, Mandigers CM, Soesan M, Beijnen JH, Schellens et al.Link to PubMed
Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data
(2015) Lancet Oncol. Oct 21. pii: S1470-2045(15)00286-7. doi: 10.1016/S1470-2045(15)00286-7. [Epub ahead of print]
Meulendijks D, Henricks LM, Sonke GS, Deenen MJ, Froehlich TK, Amstutz U, Largiadèr CR, Jennings BA, Marinaki AM, Sanderson JD, Kleibl et al.Link to PubMed
Recent publications View All Publications
First-in-human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-kinase inhibitor, in Patients with Advanced Solid Tumor Malignancies
(2015) Clin Cancer Res. Nov 24. pii: clincanres.1665.2015. [Epub ahead of print]
Munster PN, Aggarwal R, Hong D, Schellens JH, van der Noll R, Specht J, Witteveen PO, Werner T, Dees EC, Bergsland EK, Agarwal N, Kleha...Link to PubMed
EpCAM-based flow cytometry in cerebrospinal fluid greatly improves diagnostic accuracy of leptomeningeal metastases from epithelial tumors
(2015) Neuro Oncol. Nov 12. pii: nov273. [Epub ahead of print]
Milojkovic Kerklaan B, Pluim D, Bol M, Hofland I, Westerga J, van Tinteren H, Beijnen JH, Boogerd W, Schellens JH, Brandsma D.Link to PubMed
Mirna Ekelschot - van Diermen
+31 20 512 9127
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