Sub theme 1.7
Localisation, detection and radionuclide therapy of various diseases


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

Workgroup leaders   Department
prof.dr.  M.  Hendriks-de Jong   Radiation Oncology

Goals of research: general outline

1) Visualisation and radionuclide therapy of tumours and other lesions using different radiopharmaceuticals, and especially radiolabelled peptides. 

2) Molecular imaging of lesions with focus on PET and SPECT, also in combination with anatomical imaging (CT and MRI).

Description:

The research program of the department of Nuclear Medicine of the Erasmus MC focuses with success since more than 15 years on peptide receptor-targeted imaging (PRI, using positron emission tomography (PET) and single photon emission computed tomography (SPECT)) and peptide receptor-targeted radionuclide therapy (PRRT) of receptor-positive cancers using radiolabelled peptides. In that period selective receptor-targeting radiopeptides have emerged as an important class of radiopharmaceuticals for molecular imaging and therapy of tumours that overexpress peptide receptors on the cell membrane. After such peptides labeled with gamma-emitting radionuclides bind to their receptors, they allow visualization of receptor-expressing tumors non-invasively. Peptides labeled with beta-particle emitters could also eradicate receptor-expressing tumors.

Using radiolabelled somatostatin analogues we imaged over 5000 patients, whereas over 1500 treatments were given to patients suffering from mostly metastasized neuroendocrine tumours. Our efforts now concentrate on widening the therapeutic window by increasing the tumour radiation dose and/or decreasing the dose to the normal, healthy, organs. Finally we aim at curing these now incurable metastasized cancers.

To enlarge the panel of tumours to be imaged and treated, we designed and evaluated analogues of other peptides, such as bombesin, CCK, and neurotensin analogues, that bind to their receptors in a variety of different tumours.


Scientific achievements

Time line of most important PRI and PRRT events:

 

1987

1st PRI study with radioiodinated octreotide

1989

1st PRI study with OctreoScan (Indium-111 labelled octreotide)

1992

1st PRRT study with high dose Indium-111 labelled octreotide

1998

Octreotate for PRI and PRRT in preclinical studies

2000

1st clinical PRRT study with Lutetium-177 octreotate

2002

Kidney protection during PRRT using lysine and arginine

2005

500 PRRTs using Lutetium octreotate

2007

Start PRRT with Lutetium octeotate plus capacetabine

2005

Introduction and validation of animal SPECT/CT

2008

Introduction and validation of animal PET

Targeting of the somatostatin receptor in neuroendocrine tumours was our first success, we evaluated various somatostatin analogues for PRI and PRRT, e.g. [Indium-111-DTPA]octreotide, now commercially available and worldwide used for imaging and staging of neuroendocrine tumours, and the second and third generation analogues [DOTA,Tyr3]octreotide and [DOTA,Tyr3]octreotate. A phase I/II radionuclide therapy study with [Lutetium-177-DOTA,Tyr3]octreotate is ongoing in our institution, with > 75% response rate, improved quality of life and median times to progression and survival of at least 4 years obtained. Recently, a multi centre study has been initiated and the combination treatment using capecitabine and Lu-177-octreotate has been introduced.
We have gained wide experience within our group in the fields described above, covering a wide range of expertise and techniques in both basic and clinical research, which resulted in more than 200 peer-reviewed articles in this field.
Collaborations have been started and grants have been obtained in the fields of kidney protection during PRRT, development of new analogues of bombesin and CCK, and multimodality molecular imaging using SPECT, CT and MRI.


Future plans: special goals and approach

1.            Optimization of imaging quality (PET-CT, SPECT-CT in clinic and preclinic, combinations with MRI). Use of own cyclotron products for PET in 2012.

2.            Improvement of the therapeutic effects of radiopeptides using combination therapy

3.            Introduction of new peptides for PRI and PRRT 

Ad 1.

PET-center and cyclotron

The Dept. of Nuclear Medicine will open a new PET center with 2 new PET/CT scanners (and a SPECT/CT scanner)  in 2010. The cyclotron that will produce short-lived radionuclides, will be in use from Jan 2012.

Applied Molecular Imaging Erasmus MC (AMIE)

In 2006 the AMIE (Applied Molecular Imaging in Erasmus MC) program started, in this program the Dept. of Nuclear Medicine participates actively.  AMIE provides a platform for scientists who share an interest in state-of-the-art imaging technology and molecular imaging assays for studying biological systems. The research in the departments of Erasmus MC covers a wide range of topics. AMIE’s unique strength of lies in the fusion of superb expertise in imaging modes, availability of exclusive mouse models, and its strong links between basic, translational and patient-bound research.
AMIE’s mission is to study cells – in vitro as well as in their intact environment in living subjects – and to find new ways to diagnose diseases and to monitor therapies.

Animal Imaging Facility

In collaboration with other imaging departments in Erasmus MC a new Animal Imaging Facility (AIF) will be started from Jan 2010. The mission of this AIF is to increase the synergy in existing imaging research and to stimulate new research and collaborations in Erasmus MC in the field of multimodality imaging.

Ad 2.

Clinical studies

A multicenter trial has been started to study PRRT with Lutetium octreotate  in different patient groups, to obtain EMEA and FDA approval. In addition the combination study using Lutetium octreotate and capacetabine will be extended.

Preclinical studies

Combinations of radiopeptides and different chemotherapeutics will be studied to improve PRRT results.

Ad 3.

New peptide analogs with increased receptor binding affinity and improved stability are being developed. Use of these analogues will lead to higher accumulation of radioactivity inside tumour cells.

Many new analogues of somatostatin have been developed and widely studied; much profit can also be gained from improving peptide analogues targeting other tumour-related receptors.


Most recent publications

 

  1. de Jong, M.; Breeman, W. A.; Kwekkeboom, D. J.; Valkema, R.; Krenning, E. P. Tumor imaging and therapy using radiolabeled somatostatin analogues. Acc Chem Res 2009, 42, 873-80.
  2. Muller, C.; Schibli, R.; Krenning, E. P.; de Jong, M. Pemetrexed improves tumor selectivity of 111In-DTPA-folate in mice with folate receptor-positive ovarian cancer. J Nucl Med 2008, 49, 623-9.
  3. Kwekkeboom, D. J.; de Herder, W. W.; Kam, B. L.; van Eijck, C. H.; van Essen, M.; Kooij, P. P.; Feelders, R. A.; van Aken, M. O.; Krenning, E. P. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008, 26, 2124-30.
  4. de Visser, M.; van Weerden, W. M.; de Ridder, C. M.; Reneman, S.; Melis, M.; Krenning, E. P.; de Jong, M. Androgen-dependent expression of the gastrin-releasing peptide receptor in human prostate tumor xenografts. J Nucl Med 2007, 48, 88-93.
  5. van Essen, M.; Krenning, E. P.; Kooij, P. P.; Bakker, W. H.; Feelders, R. A.; de Herder, W. W.; Wolbers, J. G.; Kwekkeboom, D. J. Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. J Nucl Med 2006, 47, 1599-606.
  6. Capello, A.; Krenning, E. P.; Bernard, B. F.; Breeman, W. A.; Erion, J. L.; de Jong, M. Anticancer activity of targeted proapoptotic peptides. J Nucl Med 2006, 47, 122-9.
  7. de Jong, M.; Barone, R.; Krenning, E.; Bernard, B.; Melis, M.; Visser, T.; Gekle, M.; Willnow, T. E.; Walrand, S.; Jamar, F.; Pauwels, S. Megalin is essential for renal proximal tubule reabsorption of (111)In-DTPA-octreotide. J Nucl Med 2005, 46, 1696-700.
  8. de Jong, M.; Breeman, W. A.; Valkema, R.; Bernard, B. F.; Krenning, E. P. Combination radionuclide therapy using 177Lu- and 90Y-labeled somatostatin analogs. J Nucl Med 2005, 46 1, 13-7.
  9. Kwekkeboom, D. J.; Mueller-Brand, J.; Paganelli, G.; Anthony, L. B.; Pauwels, S.; Kvols, L. K.; O'Dorisio T, M.; Valkema, R.; Bodei, L.; Chinol, M.; Maecke, H. R.; Krenning, E. P. Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs. J Nucl Med 2005, 46 1, 62-6.
  10. Krenning, E. P.; Valkema, R.; Kwekkeboom, D. J.; de Herder, W. W.; van Eijck, C. H.; de Jong, M.; Pauwels, S.; Reubi, J. C. Molecular imaging as in vivo molecular pathology for gastroenteropancreatic neuroendocrine tumors: implications for follow-up after therapy. J Nucl Med 2005, 46 Suppl 1, 76-82.

People associated with sub theme 1.7: Localisation, detection and radionuclide therapy of various diseases
Name Position Department
Drs.  H.  Bergsma PhD-candidate Nuclear Medicine
MSc  R.H.  de  Blois Postdoc/junior researcher Nuclear Medicine
H.S.  Chan PhD-candidate Nuclear Medicine
Tmmaverick  Elmerdig PhD-candidate General Surgery
Ru Sex Dating  QettoE  Freefestdiz PhD-candidate General Surgery
L.M.  van der  Graaf Technician Nuclear Medicine
Ir.  H.C.  Groen Postdoc/junior researcher Nuclear Medicine
prof.dr.  M.  Hendriks-de Jong Workgroup leader within the School Radiation Oncology
Ladyofrage  Henryhop Professor not being a workgroup leader General Surgery
free bets uganda  Smooveb73  LizzieCheli Professor not being a workgroup leader LEPO, JNI
Msc  EJ  Meester PhD-candidate Nuclear Medicine
Уп&  Ladyofrage  Mvolodiyakive Technician General Surgery
JHS  Pikaart Technician Nuclear Medicine
Ir.  Z.  Rijnen PhD-candidate Radiotherapy
Bsc  S.T.  van  Tiel PhD-candidate Nuclear Medicine
My up to date ascend  Tmmaverick  vickixr69 Postdoc/junior researcher General Surgery