Clinical Oncology 3

Experimental Pharmacotherapy

Principal investigator

Dr A.J. Gelderblom

Aim and focus

The aim of our experimental pharmacotherapy program is to develop new anticancer therapies for patients with solid tumours and to improve outcome of therapy through development and implementation of predictive biomarkers. The program is focused on, but not limited to, early clinical drug development including pharmacokinetics, pharmacogenomics in any stage of drug development in solid tumours and treatment of sarcoma.  

Position in international context

Early drug development networks include single institutions such as academic institutions, as well as through participation within collaborative groups such as the European Organisation of Research and Treatment of Cancer Network of Core Institutions. Confirmative pharmacogenomic studies are being performed in collaboration with individual researchers as well as through an international pharmacogenomics consortium. Implementation of testing has been initiated together with medical diagnostics industry. For pharmacokinetic studies collaboration exists with St Jude’s Hospital USA. For sarcoma, research participation is guaranteed through active participation and leading positions in several international networks such as EORTC Soft Tissue and Bone Sarcoma Group, Eurobonet and European Osteosarcoma Intergroup. 

Content / highlights / achievements

Current efforts comprise “first-in-man” phase I studies with new classes of anticancer drugs with extensive translational programs and local chemotherapy perfusion studies. Translation of preclinical knowledge into systemic anti-cancer treatment has been successful in sarcoma due to the fact that LUMC is a reference center for sarcoma based on good (pre)clinical cooperation between departments, such as (orthopedic) surgery, radiology, pathology and pediatrics.

Several investigator initiated phase 4 studies, including pharmacologic interaction studies, have been successfully undertaken. Pharmacogenomic research includes a large cohort of metastatic colorectal cancer patients treated with palliative chemotherapy in 3 successive nation-wide phase III studies (CAIRO I-III) and a retrospective (TEAM) and prospective (CYPTAM) study in breast cancer aiming at prediction of hormonal therapy in breast cancer. Due to the large cohorts with access to replication cohorts these predictive studies are not only hypothesis generating, but also potentially confirmative.

Future Themes

Expansion of phase I quality and capacity is planned through a Clinical Research Unit and Good Research Practice Committee, of which the latter was recently initiated. Further collaboration within the Leiden bioscience park (CHDR and LACDR) is in development (Leiden Center of Translational Drug Discovery and Development). Pharmacokinetic analysis expertise for research purposes has been initialized. Some pharmacogenomic studies are at last stage preceding implementation in clinical practice. New projects on identification of molecular targets and proof of concept studies in sarcoma are being undertaken.

Cohesion within LUMC

Main collaborators are the department of Clinical Pharmacy and Toxicology (pharmacogenomics and drug interaction studies) and the department of Pathology (sarcoma). Collaborations with other departments in the LUMC include orthopedic surgery, surgery, pediatrics, pulmonology, radiology, nephrology, endocrinology, thoracic surgery and dermatology. Translational immunotherapy oriented projects within the field of experimental pharmacotherapy have been initialized in collaboration with the Medical Oncology laboratory (e.g. NK cell targeting in sarcoma) in order to achieve synergy with the other research line within our own department.

Key publications

Pander J, Gelderblom H, Guchelaar HJ. Pharmacogenetics of EGFR and VEGF inhibition. Drug Discov Today 23-24, 1054-1060, 2007
IF 6.62 

van Erp N, Gelderblom H, Karlsson M, Li J, Zhao M, van der Straaten T, Ouwerkerk J, Nortier JWR, Guchelaar HJ, Sparreboom A, Baker SD. Influence of cytochrome P-450 3A4 inhibition on the steady state pharmacokinetics of imatinib. Clin Cancer Res 13, 7394-400, 2007
IF 6.49 

Swen JJ, Huizinga TW, Gelderblom H, de Vries EGE, Assendelft WJJ, Kirchheiner J, Guchelaar H-J. Translating pharmacogenomics: challenges on the road to the clinic. PLoS Medicine 4, e209, 2007
IF 12.19 

Steeghs N, Gelderblom H, Roodt JO, Christensen O, Rajagopalan P, Hovens M, Putter H, Rabelink TJ, de Koning E. Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. Clin Cancer Res 14, 3470-6, 2008
IF 6.49 

Gelderblom H, Hogendoorn PC, Dijkstra SD, van Rijswijk CS, Krol AD, Taminiau AH, Bovée JV. The clinical approach towards chondrosarcoma. Oncologist 13, 320-9, 2008
IF 6.63

van Erp, Gelderblom H, van Glabbeke M, van Oosterom A, Verweij J, Guchelaar H-J, Debiec-Rychter M, Peng B, Blay J-Y, Judson I. Effect of cigarette smoking on the pharmacokinetics, safety and efficacy of imatinib: a study based on data of the Soft tissue and Bone Sarcoma Group of the EORTC. Clin Cancer Res 14, 8308-8313, 2008
IF 6.49

Dezentjé V, Guchelaar H-J, Nortier JWR, van de Velde CJH, Gelderblom H. Clinical implications of  CYP2D6 genotyping in tamoxifen treatment for breast cancer. Clin Cancer Res 15, 15-21, 2008
IF 6.49

van Erp N, Eechoute K, van der Veldt AA, Haanen JB, Reyners AKL, Mathijssen RHJ, Boven E, van der Straaten T, Baak-Pablo R, Wessels JAM, Guchelaar HJ, Gelderblom H. Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J Clin Oncol, 2009
IF 17.16

Steeghs N, Eskens FALM, Gelderblom H, Verweij J, Nortier JWR, Ouwerkerk J, van Noort C, Mariani,M, Spinelli R, Carpinelli P, LAffranchi B, de Jonge MJA. Pharmacokinetic and pharmacodynamic study of the Aurora kinase inhibitor PHA-739358 in patients with advanced or metastatic solid tumors. J Clin Oncol, in press, 2009.
IF 17.16

Eskens FALM, Steeghs N, Verweij J, Bloek JL, Christensen O, van Doorn L, Ouwerkerk J, de Jonge MJA, Nortier JWR, Kraetzschmar J, Rajagopalan P, Gelderblom H. A phase I dose escalation study of telatinib (BAY 57-9352), a tyrosine kinase inhibitor of VEGFR-2, VEGFR-3, PDGFR-β and C-Kit in patients with advanced or metastatic solid tumors. J Clin Oncol, in press, 2009.
IF 17.16