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Research Clinical and Experimental Neuroendocrinology

Goals of research and scientific achievements

Goals of research: general outline

 

This program studies disorders in neuro-endocrinology, neuro-immunology, and endocrine oncology. It develops new modalities for molecular imaging and treatment using peptide receptors as primary targets and wants to unravel the endocrine and immunological basis of important diseases in the community. Other studies are aimed to unravel the effects of genetic variations in glucocorticoid receptors and IGF-I receptors on various aspects of health, ageing and disease. A central focus in the above research are peptide hormone receptors, glucocorticoid receptors and IGF-I and insulin receptors. The aim is to work from the bench to the patient and back.

 

Scientific achievements during the last 5 years

 

Pituitary tumors

  • A detailed functional characterization of dopamine and somatostatin receptors in ACTH producing pituitary tumors from patients with Cushing’s disease has led to the initiation of clinical trials in which the efficacy of dopamine agonists (e.g. cabergoline) and novel somatostatin analogs (e.g. SOM230), alone or in combination are being tested. Promising results of a clinical trial conducted at the Erasmus MC with this combination of drugs were recently obtained.
  • We played a pivotal role in the development of the use of the growth hormone receptor antagonist pegvisomant in the treatment of acromegalic patients with growth hormone secreting pituitary tumors. A crucial observation has been the combination treatment with pegvisomant once weekly and somatostatin analogs.
  • We demonstrated antitumor activity of novel somatostatin-dopamine chimeric ligands in clinically non functioning pituitary tumors.

(Neuro)-endocrine tumors

  • We demonstrated that epigenetic changes in neuroendocrine (carcinoid) tumor cells influence tumor cell sensitivity to drug treatment with somatostatin analogs and dopamine agonists. Treatment of tumor cells with epigenetic drugs enhances the antitumor activity of somatostatin analogs and dopamine agonists.
  • We demonstrated that type I interferon’s, in particular interferon-beta, are highly potent inhibitors of adrenocortical tumor cell growth, alone and in combination with the current drug of choice, mitotane.
  • We demonstrated that type I interferon’s, in particular interferon-beta, are highly potent inhibitors of gastroenteropancreatic neuroendocrine tumor cells.  

Receptor targeted (drug) delivery

  • We have developed novel photosensitizer coupled somatostatin analogs for somatostatin receptor targeted photodynamic therapy. In vitro proof of concept studies showed receptor specific targeting resulting in cell death of somatostatin receptor expressing tumor cells. Such novel molecules are of potential interest for the treatment of somatostatin receptor expressing tumors (e.g. pituitary tumors) and different types of immune diseases (e.g. rheumatoid arthritis).
  • Targeted therapy of neuroendocrine tumors with radiolabeled somatostatin analogs. Clinical trials in humans proved to be promising.

IGF-I and insulin receptors in health and disease

  • We developed highly sensitive bioassays for IGF-I- and insulin receptors A and B.  These assays will help to further unravel the observed apparent discrepancies between IGF-I and insulin levels measured by immune assay and their respective bioactivities in physiology and endocrine oncology. We established normal values of circulating IGF-I bioactivity in the healthy population. In addition, we demonstrated that low circulating IGF-I bioactivity is associated with extended survival and reduced cardiovascular risk.

Glucocorticoid sensitivity in man (see elsewhere on this website)        

 

 

Future plans; specific goals

 

Pituitary and (neuro)-endocrine tumors

  • Development of novel peptide hormone analogs to target specific receptor (subtypes) in order to improve diagnosis and treatment of a variety of disorders (from pituitary diseases to diabetes and from rheumatism to many cancers).
  • Most likely, the optimal medical treatment of (neuro)-endocrine tumors is combination treatment. We will study the role of combination treatment with somatostatin analogs, dopamine analogs and small molecule inhibitors (IGF-I receptor inhibitors, mTOR inhibitors).
  • To further unravel the efficacy and mechanism of action of novel chimeric somatostatin-dopamine hybrid molecules on neuro-endocrine tumors.
  • To further unravel the epigenetic mechanisms involved in resistance of tumor cells to drug (e.g. somatostatin analogs and/or dopamine agonists) treatment.
  • To further explore medical treatment opportunities in adrenocortical cancer
  • Both in vitro and in vivo studies are anticipated

Receptor targeted drug delivery

  • To further develop novel photosensitizer coupled somatostatin analogs with enhanced biological activity.
  • To further develop the concept of receptor targeted delivery of drugs (e.g. small molecule inhibitors coupled to somatostatin analogs)
  • Both in vitro and in vivo animal studies are anticipated

IGF-I and insulin receptors in health and disease

  • To further unravel the role of the IGF-I and insulin receptor bioactivity in health and disease. These studies will include population based studies, as well as studies on the potential significance of measuring IGF-I and insulin receptor bioactivity in (endocrine) oncology.

 

Who is who?

 

Scientific staff laboratory

 

Leo J. Hofland, Ph.D., Professor of Experimental Neuroendocrinology, Head Laboratory Internal Medicine.

l.hofland@erasmusmc.nl

 

 

Clinical Staff

 

Steven W.J. Lamberts, M.D., Ph.D., Professor of Endocrinology

s.w.j.lamberts@erasmusmc.nl

 

Aart-Jan van der Lelij, M.D., Ph.D., Professor of Endocrinology

a.vanderlelij@erasmusmc.nl

 

Joop A.M.J.L Janssen, M.D., Ph.D., Endocrinologist

j.a.m.j.l.janssen@erasmusmc.nl

 

Richard A. Feelders, M.D., Ph.D., Endocrinologist

r.feelders@erasmusmc.nl

 

Sebastian J.C.M.M. Neggers, M.D., Ph.D., Endocrinologist

s.neggers@erasmusmc.nl

 

Wouter W. de Herder, M.D., Ph.D., Porfessor of Endocrine Oncology

w.w.deherder@erasmusmc.nl

 

 

Technical Staff

 

Peter M. van Koetsveld

p.vankoetsveld@erasmusmc.nl

 

Fadime Dogan

f.dogan@erasmusmc.nl

 

 

Ph.D. Students

 

Amber Blaauwboer

a.blaauwboer@erasmusmc.nl

   

Anela Blazevic

a.blazevic.1@erasmusmc.nl

 

Mesut Savas

m.savas@erasmusmc.nl

 

Eline van der Valk

e.vandervalk@erasmusmc.nl

 

Doctoral theses (since 2003)

 

Neggers S.J.C.M.M.

New insights into the medical treatment of acromegaly

Promotor: A.J. van der Lelij

PhD thesis EUR 10-06-2011

 

Brugts M.P.

IGF-I bioactivity in aging, health and disease

Promotor: Lamberts, prof. dr. S.W.J.

Co-promotor: Janssen, dr. J.A.M.J.L.

PhD thesis EUR 06-01-2010

 

 

Van der Hoek J.

The functional role of somatostatin receptor subtypes in pituitary adenomas

Promotor: Lamberts, S.W.J.

Co-promotor: L.J. Hofland

PhD thesis EUR 17-05-2006

 

Pivonello R.

Dopamine receptor expression and function in the normal and pathological hypothalamus-pituitary-adrenal axis

Promotor: Lamberts, S.W.J.

Co-rpomotor: L.J. Hofland

PhD thesis EUR 09-11-2005

 

V.A.S.H. Dalm VASH

Somatostatin receptors and their ligands in the human immune system.  

Promotor: Lamberts SWJ

Co-promotors: van Hagen PM, Hofland LJ.

PhD thesis EUR 01-10-2003

 

Additional Links

 

The Pituitary Center Rotterdam

http://www6.erasmusmc.nl/cs-patientenzorg/5761/273311/hypofyse.centrum

 

Neuroendocrine tumors www6.erasmusmc.nl/inwendige_geneeskunde/endocrinologie/organisatie/dokter/2355745/

 

Publications (15 selected)

 

 

1.                  Lamberts SW, van der Lely AJ, de Herder WW, and Hofland LJ. Octreotide. N Engl J Med 1996; 334:246-54.

2.         Feenstra J, de Herder WW, ten Have SM, van den Beld AW, Feelders RA, Janssen JA, and van der Lely AJ. Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly. Lancet 2005;365:1644-6.

3.         Pivonello R, Ferone D, Lamberts SW, and Colao A. Cabergoline plus lanreotide for ectopic Cushing's syndrome. N Engl J Med 2005;352:2457-8.

4.         van Koetsveld PM, Vitale G, de Herder WW, Feelders RA, van der Wansem K, Waaijers M, van Eijck CH, Speel EJ, Croze E, van der Lely AJ, Lamberts SW, and Hofland LJ. Potent inhibitory effects of type I interferons on human adrenocortical carcinoma cell growth. J Clin Endocrinol Metab 2006;91:4537-43. 

5.         Vitale G, de Herder WW, van Koetsveld PM, Waaijers M, Schoordijk W, Croze E, Colao A, Lamberts SW, and Hofland LJ. IFN-beta is a highly potent inhibitor of gastroenteropancreatic neuroendocrine tumor cell growth in vitro. Cancer Res 2006;66:554-62.

6.         Ferone D, de Herder WW, Pivonello R, Kros JM, van Koetsveld PM, de Jong T, Minuto F, Colao A, Lamberts SW, and Hofland LJ. Correlation of in vitro and in vivo somatotropic adenoma responsiveness to somatostatin analogs and dopamine agonists with immunohistochemical evaluation of somatostatin and dopamine receptors and electron microscopy. J Clin Endocrinol Metab 2008;93:1412-7.

7.         Neggers SJ, van Aken MO, de Herder WW, Feelders RA, Janssen JA, Badia X, Webb SM, and van der Lely AJ. Quality of life in acromegalic patients during long-term somatostatin analog treatment with and without pegvisomant. J Clin Endocrinol Metab 2008;93:3853-9.

8.         de Bruin C, Pereira AM, Feelders RA, Romijn JA, Roelfsema F, Sprij-Mooij DM, van Aken MO, van der Lelij AJ, de Herder WW, Lamberts SW, and Hofland LJ. Coexpression of dopamine and somatostatin receptor subtypes in corticotroph adenomas. J Clin Endocrinol Metab 2009;94:1118-24.

9.         Caraglia M, Marra M, Tagliaferri P, Lamberts SW, Zappavigna S, Misso G, Cavagnini F, Facchini G, Abbruzzese A, Hofland LJ, and Vitale G. Emerging strategies to strengthen the anti-tumour activity of type I interferons: overcoming survival pathways. Curr Cancer Drug Targets 2009; 9:690-704.

10.       Pivonello R, De Martino MC, Cappabianca P, De Leo M, Faggiano A, Lombardi G, Hofland LJ, Lamberts SW, and Colao A. The medical treatment of Cushing's disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab 2009;94:223-30.

11.       Brugts MP, van den Beld AW, Hofland LJ, van der Wansem K, van Koetsveld PM, Frystyk J, Lamberts SW, and Janssen JA. Low circulating insulin-like growth factor I bioactivity in elderly men is associated with increased mortality. J Clin Endocrinol Metab 2008;93:2515-22.

12.       Brugts MP, van Duijn CM, Hofland LJ, Witteman JC, Lamberts SW, and Janssen JA. Igf-I bioactivity in an elderly population: relation to insulin sensitivity, insulin levels, and the metabolic syndrome. Diabetes 2010; 59:505-8.

13.       Feelders RA, de Bruin C, Pereira AM, Romijn JA, Netea-Maier RT, Hermus AR, Zelissen PM, van Heerebeek R, de Jong FH, van der Lely AJ, de Herder WW, Hofland LJ, and Lamberts SW. Pasireotide alone or with cabergoline and ketoconazole in Cushing's disease. N Engl J Med 2010; 362:1846-8.

14.       Hofland LJ, Feelders RA, de Herder WW, and Lamberts SW. Pituitary tumours: the sst/D2 receptors as molecular targets. Mol Cell Endocrinol 2010; 326:89-98.

15.       Varewijck AJ, Lamberts SW, Uitterlinden P, Hofland LJ, and Janssen JA. IGF-I Bioactivity Better Reflects Growth Hormone Deficiency than Total IGF-I. J Clin Endocrinol Metab 2011, 96: 2248-54.