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| Invited Talk, Friday, 14:30 – 15:00 |
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| Peptides Hormones: Tools and
Drugs in Therapy and Diagnosis of Breast Cancer
Annette G. Beck-Sickinger
University of Leipzig, Institute
of Biochemistry, Brüderstraße 34, 04103 Leipzig, Germany |
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| Contact:
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Peptides hormones play an important role in the regulation of manifold
activities in the body. Most of them bind to G-protein coupled receptors
and transmit activity via G-protein mediated signaling systems. In addition
to their physiological function many peptides are involved in the regulation
of tumour growths as tumours frequently express their receptors. However,
as agonist-induced internalization of G protein-coupled receptors plays
an important role in signal regulation, these properties can be easily
used to shuttle agonist-conjugates selectively into tumour cells.
Neuropeptide Y is a 36 amino acid peptide hormone and binds to so-called
Y-receptors. Whereas normal breast tissue expresses exclusively Y2 receptor
subtypes, it has been shown that tumour cells and breast cell metastasis
express Y1 receptors in high numbers [1]. Neoplastic changes accordingly
correlate with a change in receptor subtype expression. We recently could
show that this system can be used to selectively label tumors in patients
[2]. By developing Y1 receptor selective peptides [3] and subsequent labeling
with radioactive conjugates [4] or chemotherapeutics [5] this approach
suggests a novel tumour specific targeting of breast cancer [6]. The underlying
mechanisms of the internalization of the human neuropeptide Y receptors
[7] as well as their desensitization, endocytosis and resensitization is
however mainly unknown and suggests that the biophysical properties of
cells may influence the success of this approach.
The manifold possibilities to modify peptides have allowed us to develop
several analogues to target breast cancer tumours in cells, animals and
in first studies in patients.
| [1] |
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Körner M, Reubi JC: NPY
receptors in human cancer: a review of current knowledge, Peptides
28: 419-25 (2007). |
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| [2] |
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Khan IU, Zwanziger D, Böhme I,
Javed M, Naseer H, Hyder SW, Beck-Sickinger AG: Breast-cancer
diagnosis by neuropeptide Y analogues: from synthesis to clinical application,
Angew Chem Int Ed Engl. 49: 1155-8 (2010). |
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| [3] |
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Zwanziger D, Böhme I, Lindner D,
Beck-Sickinger AG: First selective
agonist of the neuropeptide Y1-receptor with reduced size, J Pept
Sci. 15: 856-66 (2009). |
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| [4] |
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Zwanziger D, Khan IU, Neundorf I, Sieger
S, Lehmann L, Friebe M, Dinkelborg L, Beck-Sickinger AG: Novel
chemically modified analogues of neuropeptide Y for tumor targeting,
Bioconjug Chem. 19: 1430-8 (2008). |
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| [5] |
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Ahrens VM, Frank R, Stadlbauer S, Beck-Sickinger
AG, Hey-Hawkins E: Incorporation
of ortho-carbaboranyl-Nepsilon-modified L-lysine into neuropeptide Y receptor
Y1- and Y2-selective analogues, J Med Chem. 54: 2368-77 (2011). |
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| [6] |
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Zwanziger D, Beck-Sickinger AG: Radiometal
targeted tumor diagnosis and therapy with peptide hormones, Curr
Pharm Des. 14: 2385-400 (2008). |
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| [7] |
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Walther C, Mörl K, Beck-Sickinger
AG: Neuropeptide Y receptors:
ligand binding and trafficking suggest novel approaches in drug development,
J Pept Sci. 17: 233-46 (2011). |
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