The present invention overcomes pitfalls inherent in the prior art by providing novel compositions and methods for their use in treatment of prostate and breast cancers. The invention provides novel synthetic peptides, which exhibit anti-androgen receptor activity to be used in human prostate and/or breast cancer therapy or prevention. These peptides contain proline stretches, which have been implicated to play a major role in the interaction of AR with the SH3 domain of the tyrosine kinase src and, eventually, other src-family kinases. The SH3 domains are 50-70 amino acid long and can be often recognized in eukaryotic signal transduction and cytoskeletal proteins (Kay et al., 2000). They bind proline rich peptides, and, through such an interaction, play a major role in regulation of kinase activity as well as localization and substrate recognition. Each src kinase family members has in its sequences a SH3 domain. The members of this familiy are nine (Williams et al, 1998) and others might be identified in the future. Agonist occupied androgen and progesterone receptors have been reported to be able of interaction with the SH3 domain of src (Migliaccio et al., 2000; Boonyaratanakornkit et al., 2001). These associations probably remove the inhibitory action of the SH3 domain and trigger Src activation. In such a way disclosed peptide(s) bind to SH3 domain of src and prevent AR from interacting with src and from activating signal transduction. It has been reported that androgen and estradiol receptors are associated under basal conditions (Migliaccio et al., 2005). When one of the two receptors is activated either by a steroid agonist or a growth factor, the two receptors interact with src. Therefore, prevention of AR association with src also prevents ER association with this kinase and src activation by ER. As a consequence, peptides disclosed herein also have an anti-estrogenic action.

ANTI-ANDROGEN PEPTIDES AND USES THEREOF IN CANCER THERAPY

MIGLIACCIO, Antimo
2008

Abstract

The present invention overcomes pitfalls inherent in the prior art by providing novel compositions and methods for their use in treatment of prostate and breast cancers. The invention provides novel synthetic peptides, which exhibit anti-androgen receptor activity to be used in human prostate and/or breast cancer therapy or prevention. These peptides contain proline stretches, which have been implicated to play a major role in the interaction of AR with the SH3 domain of the tyrosine kinase src and, eventually, other src-family kinases. The SH3 domains are 50-70 amino acid long and can be often recognized in eukaryotic signal transduction and cytoskeletal proteins (Kay et al., 2000). They bind proline rich peptides, and, through such an interaction, play a major role in regulation of kinase activity as well as localization and substrate recognition. Each src kinase family members has in its sequences a SH3 domain. The members of this familiy are nine (Williams et al, 1998) and others might be identified in the future. Agonist occupied androgen and progesterone receptors have been reported to be able of interaction with the SH3 domain of src (Migliaccio et al., 2000; Boonyaratanakornkit et al., 2001). These associations probably remove the inhibitory action of the SH3 domain and trigger Src activation. In such a way disclosed peptide(s) bind to SH3 domain of src and prevent AR from interacting with src and from activating signal transduction. It has been reported that androgen and estradiol receptors are associated under basal conditions (Migliaccio et al., 2005). When one of the two receptors is activated either by a steroid agonist or a growth factor, the two receptors interact with src. Therefore, prevention of AR association with src also prevents ER association with this kinase and src activation by ER. As a consequence, peptides disclosed herein also have an anti-estrogenic action.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11591/160075
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