Sub theme 1.1
Clinical and expirimental neuroendocrinology

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

Workgroup leaders   Department
dr  L.J.  Hofland   Endocrinology
Dr.  R.P.  Peeters   Internal Medicine

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

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 receptors in health and disease

  • We identified a number of polymorphisms in the glucocorticoid receptor (GR)-gene that are associated with changes in glucocorticoid sensitivity. Several studies have identified the effects of these genetic variations on various aspects of health and ageing and disease (e.g. obesity, dementia, depression, cardiovascular disease).        

Future plans: special goals and approach

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.

Glucocorticoid receptors in health and disease

  • To further unravel the molecular basis of peptide and steroid hormone receptor gene mutations and polymorphisms for improvements in the prevention and selective treatment of important diseases such as e.g. obesity, diabetes and hypertension.

Most recent publications

1.     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. [IF 28.4]

2.     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. [IF 50.0]

3.     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.  [IF 6.3]

4.     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. . [IF 7.5]

5.     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. [IF 6.3]

6.     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. [IF 6.3]

7.     van den Akker EL, Koper JW, van Rossum EF, Dekker MJ, Russcher H, de Jong FH, Uitterlinden AG, Hofman A, Pols HA, Witteman JC, and Lamberts SW. Glucocorticoid receptor gene and risk of cardiovascular disease. Arch Intern Med 2008;168:33-9. [IF 9.1]

8.     de Bruin C, Pereira AM, Feelders RA, Romijn JA, Roelfsema F, Sprij-Mooij DM, van Aken MO, van der Lely 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. [IF 6.3]

9.     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. [IF 6.3]

10. 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. [IF 6.3]