RETRO-INVERSO PEPTIDE INHIBITORS IN THE METASTATIC PROCESS
Cell migration offers rich targets for intervention and its control is considered an attractive approach for the clinical management of pathologic conditions sustained by deregulated cell migration mechanisms, including neoplastic diseases, disorders related to neo-vascularization as well as chronic inflammation. The present invention concerns retro-inverso (RI) peptides that are potent inhibitors of cell migration, invasion and angiogenesis, and are stable in human serum. The molecular mechanism underlying their inhibitory effect is known to us in detail: they recognize with high affinity the formyl-peptide receptor type 1, preventing receptor internalization and signaling.
Currently available cancer therapies are limited by progression to a phenotype resistant to cytotoxic therapies, and by consequent uncontrolled tumor spread and metastatic dissemination. The present invention concerns retro-inverso (RI) peptides that prevent three key events occurring during the metastatic process: invasion of the extracellular matrix, formation of a capillary network, and the entry of tumor cells into bloodstream. The compounds of the invention can be used for prevention and treatment of local and metastatic invasion by solid tumors, including sarcoma, melanoma, breast and lung cancer cells. The compounds of the invention are also useful in the prevention and treatment of disorders related to neo-angiogenesis, and for the treatment of disorders associated with altered immune cell motility such as chronic inflammations. They may be also radiolabeled with a positron emitter for microPET imaging.
- Sarcoma, melanoma, breast and lung cancer;
- Ocular neovascularization diseases;
- Rheumatoid arthritis, psoriasis and chronic granulomatous disease;
- MicroPET imaging for the diagnosis, detection, screening and/or staging of tumors.
- Inhibit migration and extracellular matrix invasion by tumor cells;
- Inhibit in vitro and in vivo angiogenesis;
- Inhibit intravasation of tumor cells;
- Reduce in vitro and in vivo the number of circulating cancer cells;
- Prevent lung metastases by human sarcoma cells implanted in murine models.