Sub theme 3.11
Translational Pharmacology


Goals of research: general outline
Scientific achievements
Future plans: special goals and approach
Running projects
Associated staff


Goals of research: general outline

The program ‘Translational Pharmacology’ covers a broad range of topics with clinical trials involving patients on one hand, and pharmacological and biological approaches using preclinical models on the other hand. In the hospital, cancer patients are treated with classic and experimental anticancer agents covering the entire spectrum of phase I, both single agent and combination scheduling and sequencing, early and late phase II and phase III clinical studies. All stages of clinical drug development are linked to an extensive translational research program that addresses pharmacokinetics (PK) and pharmacodynamics (PD) of the investigational drugs as well as pharmacogenetics (PG) influencing these pharmacological parameters. Special attention is given to identify pre-treatment patient characteristics influencing distribution - and hence efficacy and/or toxicity - of frequently used anticancer agents in order to develop genotype and/or phenotype based dosing approaches to correct for interpatient variation. In addition, research is carried out to elucidate the molecular mechanisms of carcinogenesis and the ways (cancer) cells respond to various kinds of stress notably exposure to chemotherapeutic agents and/or DNA damaging conditions. The overall aim is to improve the systemic therapy of cancer either through the use of novel anticancer agents and/or novel combinations of chemotherapeutic compounds, the tailoring of existing treatments for specific patient populations, and the discovery of novel drug targets.

 

The program is carried out by closely interconnected research groups housed both in the Daniel den Hoed Cancer Center and the Josephine Nefkens Institute:

  • Tumor Biology / Pharmacodynamics (dr. E.A.C. Wiemer)

This research group focuses on the molecular mechanisms of drug resistance and the molecular responses of (cancer) cells to chemotherapeutic compounds/conditions with emphasis on the role of non-protein coding RNAs notably microRNAs, in these processes. In addition the group is involved in the discovery and analysis of pharmacodynamic markers in the context of clinical trials.

  • Personalized Medicine/ Pharmacokinetics and –genetics (dr. R.H.J. Mathijssen)

This research group aims to optimize the systemic exposure of individual patients to anticancer drugs by investigating how genetic influences (e.g. SNPs in genes coding for metabolizing enzymes and drug transporters), lifestyle differences, co-medication, dosing schedules etc. affect the pharmacokinetics and pharmacodynamics of the drugs. The group houses a core facility that operates in compliance with the OECD principles of good laboratory practice (GLP) and carries out all pharmacological / pharmacokinetic analyses within the dept. of Medical Oncology.

  • Early Clinical Trials (dr. M.J. de Jonge)

This research group is mainly conducting phase I and early phase II clinical trials with newly developed anticancer agents. These trials are either initiated by Erasmus MC researchers or by third parties (e.g. the pharmaceutical industry, EORTC). The unit of clinical trial and research coordination (i.e. the trial office medical oncology, research nurses and hereditary cancer research office) operates within this research group to facilitate and support the clinical scientific research within the dept. of Medical Oncology. 

  • Genito-Urinary Oncology (dr. R. de Wit)

This research group is involved in both early and late drug development in genitourinary cancers. In this theme there is an unique clinical and translational research collaboration between the departments of Medical Oncology, Urology and Pathology. Innovative bench to bedside research programs are carried out in prostate cancer, urothelial cell cancer of the urinary tract, renal cell cancer and germ cell (testicular) cancer.


Scientific achievements
  • Over the last five years the ‘Translational Pharmacology’ program resulted in more than 100 original publications in (highly ranked) peer-reviewed journals, over 100 presentations at scientific meetings and nine PhD-theses. In addition, we coordinated and performed over 75 phase I and early phase II clinical trials investigating the toxicity and efficacy of novel anticancer agents. The phase I and early phase II studies are typically conducted in late stage disease patients; not restricted to primary site, and for whom standard treatment options no longer exists, whereas phase II and III clinical studies are organ specific. In the majority of these studies PK, PD and PG sampling was carried out for further/future analyses and for use in subsequent studies.
  • We intensively studied the influence of body size measures on the pharmacokinetics of cytotoxic agents used in daily oncology practice. Correcting the dose for body-surface area (BSA) does not result in a significant decrease of the inter-individual pharmacokinetic variability in the majority of cases. This means that the primary rationale to use BSA for dosing these drugs has become invalid. Consequently, this also means that useful alternatives have to be found to replace BSA-based dosing.
  • Several approaches (modulation of CYP3A and ABCB1; therapeutic drug monitoring) were examined to optimize docetaxel treatment by reducing the interpatient variability. Some developed strategies are currently refined to make them clinically applicable. In addition, using both genotyping and phenotyping strategies as well as pharmacological prophylactic interventions, several ways to improve irinotecan tolerability were investigated. Dosing strategies, based on the most relevant parameters for predicting drug metabolism, are currently tested in prospective trials.
  • We have introduced the use of microdialysis in oncology, both in preclinical animal models for prostate cancer as well in oncological patients, in order to be able to determine the intratumoral concentrations of unbound anticancer drugs.
  • A microRNA profiling platform based on the use of LNA™ modified oligonucleotides was developed and is currently used to study the role of miRNAs in the DNA damage response, in cell death pathways, in hypoxia and in several cancer types notably non-small cell lung cancer, colorectal cancers and premalignant lesions and sarcomas (liposarcomas, leiomyosarcomas, gastrointestinal tumors).

Future plans: special goals and approach
  • As clinical trails are a key and central activity within the program Translational Pharmacology we plan to continue and expand the clinical trial program focussing on novel targeted compounds, innovative clinical formulations and new combinations of experimental and classic anticancer compounds. The objective is to contribute to the development of novel, efficient and improved anticancer therapies. Whenever possible PK, PD and PG sampling / analyses will be integrated parts of the trials.
  • By performing carefully planned clinical studies we want to determine the most important factors influencing systemic exposure to anti-cancer drugs. Unexpected adverse events and relevant side-effects of new compounds are studied in detail, often resulting in a better understanding of the mechanisms behind these phenomena. Next, we will (try to) incorporate this new knowledge in future dosing strategies.
  • From preclinical studies involving primary and cancer cell lines and cancer samples we aim to identify and characterize protein coding and non protein coding (e.g. miRNA) genes essential for carcinogenesis and the response / sensitivity to chemotherapeutic agents / conditions. In subsequent in vivo studies (transgenic and KO mouse models, xenografts) as well clinical studies we will examine the possible therapeutic potential of a selected set of genes.

Most recent publications
  1. Burger, H, van Tol, H., Boersma, A.W.M., Brok, M., Wiemer, E.A.C., Stoter, G. and Nooter, K. Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP) / ABCG2 drug pump. Blood 104: 2940-42, 2004.
  2. Tannock, I.F., de Wit, R., Berry, W.R., Horti, J., Pluzanska, A., Chi, K.N., Oudard, S., Théodore, C., James, N.D., Turesson, I., Rosenthal, M.A., and Eisenberger, M.A. Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. N. Eng. J. Med. 351: 1502-12, 2004.
  3. Mathijssen, R.H.J., de Jong, F.A., van Schaik, R.H.N., Lepper, E.R., Friberg, L.E., Rietveld, T., de Bruijn, P., Graveland, W.J., Figg, W.D., Verweij, J., and Sparreboom, A. Prediction of irinotecan pharmacokinetics by use of cytochrome P450 3A4 phenotyping probes. J. Natl. Cancer Inst. 96: 1585-92, 2004.
  4. Loos, W.J., de Jongh, F.E., Sparreboom, A., de Wit, R., van Boven-van Zomeren, D.M., Stoter, G., Nooter, K., and Verweij, J. Evaluation of an alternate dosing strategy for cisplatin in patients with extreme body surface area values. J. Clin. Oncol. 24: 1499-506, 2006.
  5. Kowalski, M.P., Dubouix-Bourandy, A., Bajmoczi, M., Golan, D.E., Zaidi, T., Coutinho-Sledge, Y.S., Gygi, M.P., Gygi, S.P., Wiemer, E.A.C., and Pier, G.B. Host resistance to lung infection mediated by major vault protein in epithelial cells. Science 317: 130-32, 2007.
  6. Van den Belt-Dusebout, A.W., de Wit, R., Gietema, J.A., Horenblas, S., Louwman, M., Ribot, J., Hoekstra, H.J., Ouwens, G., Aleman, B.M.P., and van Leeuwen, F.E. Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer (CTA). J. Clin. Oncol. 25: 4370-78, 2007.
  7. Van der Bol, J.M., Mathijssen, R.H.J., Loos, W.J., Friberg, L.E., van Schaik, R.H., de Jonge M.J., Planting, A.S., Verweij, J., Sparreboom, A., and de Jong, F.A. Cigarette smoking and irinotecan treatment: pharmacokinetic interaction and effects on neutropenia. J. Clin. Oncol. 25: 2719-26, 2007.
  8. Foekens, J., Sieuwerts, A.M., Look, M.P., de Weerd, V., Boersma, A.W.M., Meijer-van Gelder, M.E., Smid. M., Wiemer, E.A.C. and Martens, J.W.M.  MiRNAs associated with aggresiveness of hormone receptor positive human breast cancer. Proc. Natl. Acad. Sci. USA 105: 13021-26, 2008.
  9. Van Weerden, W.M., Bangma, C., and de Wit, R. Human xenograft models as useful tools to assess the potential of novel therapeutics in prostate cancer. Br. J. Cancer 100:13-18, 2009
  10. Van Erp, N.P., Eechoute, K., van der Veldt, A.A., Haanen, J.B., Reyners, A.K.L., Mathijssen, R.H.J., Boven, E., van der Straaten, T., Baak-Pablo, R.F., Wessels, J.A.M., Guchelaar, H.J., and Gelderblom, H. Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J. Clin. Oncol. Epub August, 2009.

People associated with sub theme 3.11: Translational Pharmacology
Name Position Department
Š³Š°Š·Š¾Š±Š»Š¾Šŗ  Boogieq  Aaronjew Postdoc/junior researcher General Surgery
A.A.  Aliev Other as mentioned (please specify in remarks) Internal Medicine
MD  J.T.  ARINZE PhD-candidate Cardiologie
BSc  EAB  Basak PhD-candidate Medical Oncology
MSc  L.B.  Binkhorst PhD-candidate Medical Oncology
Bsc  A.W.M.  Boersma Technician Medical Oncology
Š³Š°Š·Š¾Š±Š»Š¾Šŗ  Ladyofrage  CarlosSen Workgroup leader within the School General Surgery
MSc  E.  Clemens PhD-candidate Pediatrics Oncology
AR  Dreijer PhD-candidate Medicine
R.A.G.  van  Eerden PhD-candidate Medical Oncology
Dr.  W.W.M.  Fleuren Postdoc/junior researcher Bioinformatics
K  Ganesh MSc student (please specify in remarks) Pulmonary Diseases
MSc.  C.M.M.  Gits PhD-candidate Medical Oncology
Drs.  A.M.  de  Graan PhD-candidate Medical Oncology
jkhyfesd  Ladyofrage  HenryMug Technician General Surgery
Social pictures  Paulpeter  henrysl4 Professor not being a workgroup leader General Surgery
Dr.  S.  Hoeks Assistent professor (UD) Anaesthesiology
DP  Hurkmans PhD-candidate Medical Oncology
G.A.M.  Hussaarts PhD-candidate Medical Oncology
Drs.  N.S.  IJzerman PhD-candidate Medical Oncology
MSc  M.T.M.  van  Jaarsveld Postdoc/junior researcher Medical Oncology
EK  Kienhuis PhD-candidate Medical Oncology
EK  Kienhuis PhD-candidate Medical Oncology
Drs.  J.S.L.  Kloth PhD-candidate Medical Oncology
PhD  S.L.W.  Koolen Postdoc/junior researcher Medical Oncology
BSc  P.F.  van   Kuijk Technician Medical Oncology
R.  Lammers-Veling Other as mentioned (please specify in remarks) Management
J.  Lock PhD-candidate Hematology
drs.  F.M.  de  Man PhD-candidate Medical Oncology
P.A.J  Mendelaar MSc student (please specify in remarks) Medical Oncology
significant site  Boogieq  MiguelMeacy Physician (MD) General Surgery
C  Owusuaa PhD-candidate Medical Oncology
Thun  richeventyar Senior researcher not being a workgroup leader General Surgery
Paulpeter  Robertzex Professor not being a workgroup leader General Surgery
W.S.  van de Geer PhD-candidate Medical Oncology
MSc  LvD  Van Doorn Other as mentioned (please specify in remarks) Medical Oncology
M  Vos PhD-candidate Medical Oncology
M.Sc.  A.L.M.  Vriends Technician Medical Oncology
MSc  P.  Wander PhD-candidate Pediatrics Oncology
QettoE  Williamfut Workgroup leader within the School General Surgery
PhD  S  Zalba Oteiza Assistent professor (UD) Surgery