Research interest
The research activities of our group extends on the interface between laboratory and clinic. It focuses on (1) the identification of novel targets and agents to increase the cytotoxic effect of radiation and on (2) the validation of new endpoints to quantify and predict the efficacy and toxicity of new combination therapies. The ultimate goal is to translate these strategies into clinical application.
In close collaboration with several research groups within the NKI, new agents are identified on the basis of their mechanism of action and subsequently tested for their ability to induce apoptotic cell death and to increase the cytotoxic effect of radiation in vitro and in vivo. These include synthetic alkylphospholipids, death receptor ligands (TRAIL, CD95L), small molecule inhibitors of Bcl-2 (Gossypol) and PARP inhibitors (APO866). The oral alkyl-phospholipid Perifosine combined with radiotherapy represents a strategy that we have advanced into the clinic.
To monitor tumor response and predict treatment outcome, we explore new functional imaging modalities. For example, in vivo imaging of apoptosis by annexin V scintigraphy was shown to be successful in predicting outcome after radiotherapy and/or chemotherapy in various tumor types. This imaging modality also allows to verify the mechanism of action of novel apoptosis-modulating strategies in vivo.
Our clinical research aims at designing more efficient treatment modalities by modifying radiation schedules (dose escalation, hypofractionation, simultaneous integrated boost), by combining radiation with systemic drugs (chemotherapy, biological agents) and by reducing normal tissue toxicity (brachytherapy, breath-hold, IMRT, IGRT). To improve target delineation various functional imaging modalities are explored in collaboration with the departments of nuclear medicine and radiology. Translational research continues to focus on the identification of agents that enhance the cytotoxic effect of radiation, and of tests/biomarkers that predict treatment outcome. Recently, a randomized multicenter trial in NSCLC has been completed comparing radiation with radiation plus oral Perifosine, a potential apoptosis-modulating radiosensitizer. A large multicenter randomized phase III trial in gastric cancer investigating the role of post-operative chemoradiotherapy is recruiting patients from more than 20 centers in Europe.
Key publications
Kartachova M, van Zandwijk N, Burgers S, van Tinteren H, Verheij M, Valdes Olmos RA (2007). Prognostic Significance of 99mTc Hynic-rh-Annexin V Scintigraphy During Platinum-based Chemotherapy in Advanced Lung Cancer. J Clin Oncol 25, 2534-2539.
Wissink EHJ, Verbrugge I, Vink SR, Schader MB, Schaefer U, Walczak H, Borst J, Verheij M (2006). TRAIL enhances efficacy of radiotherapy in a p53 mutant, Bcl-2 overexpressing lymphoid malignancy. Radiother Oncol 80, 214-222.
Vink SR, Schellens JHM, Beijnen JH, Sindermann H, Engel J, Dubbelman R, Moppi G, Hillebrand MJX, Bartelink H, Verheij M (2006). Phase I and pharmacokinetic study of combined treatment with study perifosine and radiation in patients with advanced solid tumours. Radiother Oncol 80, 207-213.
Vink SR, Lagerwerf S, Mesman E, Schellens JHM, Begg AC, van Blitterswijk WJ, Verheij M (2006). Radiosensitization of squamous cell carcinoma by the alkylphospholipid Perifosine in cell culture and xenografts. Clin Cancer Res 12, 1615-1622.
Jansen EPM, Boot H, Verheij M, van de Velde CJH (2005). Optimal locoregional treatment in gastric cancer. J Clin Oncol 23, 4509-4517.
Van Blitterswijk WJ, Koning GA, van Hell A, Vink S, Zerp S, Storm G, Verheij M Veldman RJ (2005). Co-formulated N-octanoyl-glucosylceramide improves cellular delivery and cytotoxicity of liposomal doxorubicin. J Pharmacol Exp Ther 315, 705-710.
Haas R, de Jong D, Valdés Olmos RA, Zerp SF, van den Heuvel I, Bartelink H, Verheij M (2004). In vivo imaging of radiation-induced apoptosis in follicular lymphoma patients. Int J Radiat Oncol Biol Phys 59, 782-787.
Van der Luit AH, Budde M, Ruurs P, Verheij M, van Blitterswijk WJ (2002). Alkyl-lysophospholipids induce apoptosis via raft-mediated endocytosis and inhibition of phosphatidylcholine synthesis. J Biol Chem 277, 39541-39547.
Ruiter GA, Zerp SF, Bartelink H, van Blitterswijk WJ, Verheij M (1999). Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis. Cancer Res 59, 2457-2463.
Verheij M, Bose R, Lin XH, Yao B, Jarvis WD, Grant S, Birrer MJ, Szabo E, Zon LI, Kyriakis JM, Haimovitz-Friedman A, Fuks Z, Kolesnick RN (1996). Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 380, 75-79.
Bose R, Verheij M, Haimovitz-Friedman A, Scotto K, Fuks Z, Kolesnick R (1995). Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 82, 405-414.
More publications by Marcel Verheij on PubMed
Biographic sketch
Marcel Verheij (1962) received his medical degree in 1989 at the State University in Leiden. Following his Military Service, he joined the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital in Amsterdam where he did his residency in Radiation Oncology under supervision of Harry Bartelink. From 1994 until 1996 he joined the group of Zvi Fuks at Memorial Sloan-Kettering Cancer Center in New York as part of his PhD program. Here, he was involved in apoptosis research and studied the role of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) signal transduction pathway in radiation-induced apoptosis. In 1996 he received his PhD (cum laude) from the Free University in Amsterdam on Radiation Injury of the Kidney: Mechanisms and Modulation of Endothelial Dysfunction. Since 2000 he is a permanent staff radiation oncologist at the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital where he holds a 50% clinical/50% research position. He is group leader at the Division of Cellular Biochemistry and coordinator of the clinical unit for combined modality treatment. In 2004 he was appointed professor in Translational Radiotherapy at the Free University in Amsterdam and since May 2007 he chairs the Division of Radiotherapy.
The Radiotherapy Division treats over 4000 new patients each year. With currently 8 linear accelerators (4 equipped with Cone Beam CT), one substitute and one spare treatment suite, the steadily growing demand for radiotherapeutical patient care can be met. At the same time, we have invested in further improvement of the treatment quality. The use of intensity-modulated radiotherapy (IMRT) and Cone Beam CT-based image guided radiotherapy (IGRT) allows optimal sparing of normal tissues and safe treatment intensification by dose-escalation and/or the addition of cytotoxic agents. For example, the breath-hold technique in breast irradiation results in a significant dose reduction to the heart, minimizing the risk of late cardiac morbidity. By determining the exact location of the tumor before each fraction, frameless stereotactic hypofractionated radiotherapy has become an effective and patient friendly treatment option for early stage lung cancer. IMRT in rectal, anal and cervical cancer limits the radiation dose to critical normal tissues, allowing a safe combination with cytostatic drugs. An essential element of these high precision irradiation techniques is the verification of the dose delivered to the individual patient. This can be achieved by in vivo dosimetry with electronic portal imaging devices (EPID). Given the increasing complexity of the treatment plans, we have given high priority to dose verification. By the end of 2007, all curative treatments are verified by means of EPID dosimetry. A further refinement of this technology will focus on 3D dose reconstruction.
Co-workers
Berthe Aleman MD PhD Academic staff
Harry Bartelink MD PhD Academic staff
Jose Belderbos MD PhD Academic staff
Eugène Damen PhD Academic staff
Roel De Boer PhD Academic staff
Luc Dewit MD PhD Academic staff
Rick Haas MD PhD Academic staff
Olga Hamming-Vrieze MD Academic staff (temporary)
Guus Hart MSc Academic staff
Wilma Heemsbergen MSc Academic staff
Frank Hoebers MD PhD Academic staff
Edwin Jansen MD Academic staff
Han Krewinkel MSc Academic staff
Joos Lebesque MD PhD Academic staff
Corrie Marijnen MD PhD Academic staff
Harry Masselink MD Academic staff
Ben Mijnheer PhD Academic staff
Luc Moonen MD PhD Academic staff
Floris Pos MD PhD Academic staff
Coen Rasch MD PhD Academic staff
Babs Reichgelt MD Academic staff (temporary)
Peter Remeijer PhD Academic staff
Nicola Russell MD PhD Academic staff
Govert Salverda MD Academic staff
Christoph Schneider PhD Academic staff
Joep Stroom PhD Academic staff
Bart Van Bunningen MD Academic staff
Marcel Van Herk PhD Academic staff
Corine Van Vliet-Vroegindeweij PhD Academic staff
Marieke van Zwienen MD PhD Academic staff (temporary)
Frits Wittkämper PhD Academic staff
Monique Bloemers MD Temporary staff
Gerben Borst MD Temporary staff
Desiree Van den Bongard MD PhD Temporary staff
Joost Knegjens MD Temporary staff
Bas Kreike MD Temporary staff
Philip Meijnen MD PhD Temporary staff
Dimitry Nuyten MD Temporary staff
Vera Oppedijk MD Temporary staff
Roel Steenbakkers MD PhD Temporary staff
Oene Van Meer MD Temporary staff
Francine Voncken MD Temporary staff
Martijn Eenink PhD Post-doc
Marnix Maas PhD Post-doc
Anton Mans PhD Post-doc
Leah McDermott PhD Post-doc
Vanessa Mexner PhD Post-doc
Anke van Mourik PhD Post-doc
Juup Nijholt PhD Post-doc
Erik-Jan Rijkhorst PhD Post-doc
Simon Rit PhD Post-doc
Jan-Jakob Sonke PhD Post-doc
Mine Temurhan PhD Post-doc
Rajko Topolnjak PhD Post-doc
Markus Wendling PhD Post-doc
Marnix Witte PhD Post-doc
Simon van Kranen MSc Graduate student
Monique Smitsmans MSc Graduate student
Jochem Wolthaus MSc Graduate student
Robin Kalisvaart Physician Assistant
Margriet Kwint Physician assistant
Gül Yüksel Physician assistant
Anja Betgen Technical staff
Josine De Bois Technical staff
Joop Duppen Technical staff
Angelo Mencarelli Technical staff
Tom Minderhoud Technical staff
Jasper Nijkamp MSc Technical staff
Agnieszka Olszewska MSc Technical staff
Carmen Panneman MSc Technical staff
Carolien Peters Technical staff
Kenneth Pengel Technical staff
Edwin Roosjen Technical staff
Maddalena Rossi Technical staff
René Tielenburg Technical staff
Lambert Zijp MSc Technical staff
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