Development of immuno-mediated pharmacotherapy models for melanoma
Aree / Gruppi di ricerca
Partecipanti al progetto
- Dianzani Chiara (Coordinatore/trice)
- Fantozzi Roberto (Docente)
- Ferrara Benedetta (Dottorando/a)
Descrizione del progetto
Members:
Prof.ssa Giuseppina Barrera, Department of Clinical and Biological Sciences, University of Turin,
Prof.ssa Mirella Giovarelli, Department of Molecular Biotechnology and Health Sciences, University of Torino
Prof. Francesco Trotta, Department of Chemistry, University of Torino
Members of other units:
Prof. Umberto Dianzani, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, “A. Avogadro” University of Piemonte Orientale (UPO), Novara
Sponsor:
Local funds (ex_60%) University of Turin, Italy
Description:
Melanoma represents 4% of all cancers. Elevated levels of the proinflammatory cytokine Osteopontin (OPN) correlate with increased metastasis and poor prognosis in several solid tumors including melanoma. During inflammation, OPN is cleaved by thrombin in an N-terminal (OPN-N) and a C-terminal (OPN-C) fragment. OPN-N displays several binding sites for integrins; OPN-C binds to CD44.Moreover, an intracytroplasmic form of OPN (iOPN) binds Toll-like receptor-9 (TLR-9) and is a critical regulator for TLR-9 and TLR-7-dependent IFN-α expression. All available data about OPN in melanoma are related to the whole OPN, without distinguishing among the effects of its fragments and the role of iOPN, which play distinct roles in the inflammatory and anti-tumoral process by modulating cytokine secretion, adhesion, migration, and survival of tumor and immune cells. Imiquimod (IMQ) is an immune modulator via binding to TLR-7; it acts as a potent inducer of IFN-α, TNF-α, IL-1β, and IL-6 and exerts consistent antitumor effects in mice. In humans, it is used topically for the treatment of several skin cancers. The efficacy of anticancer therapies targeting OPN may be enhanced by selectively antagonizing the pro-metastatic and pro-angiogenic activities of OPN but preserving its immunostimulatory activities. Secondly, therapies targeting OPN may be used in combination with other immunotherapeutic agents, such as IMQ, acting on similar pathways. However, systemic use of IMQ requires novel delivery systems.
The aim of this project is to investigate the distinct role of the OPN-fragments and iOPN
Keywords:
Melanoma, Osteopontin, Imiquimod, Immunotherapeutic agents