Descrizione del progetto
Nuovi farmaci contro il cancro e le malattie infiammatorie
Il CXCR4 è un recettore per le chemochine implicato in diverse condizioni patologiche, tra cui il cancro e le infezioni virali. Viene attivato da CXCL12, che regola l’adesione delle cellule allo stroma e la mobilitazione delle cellule staminali ematopoietiche, e funge anche da co-recettore per l’ingresso dell’HIV nelle cellule. L’obiettivo del progetto EPI-X4Health, finanziato dall’UE, è di testare il peptide endogeno EPI-X4 per il suo potenziale terapeutico contro il cancro e le malattie infiammatorie. EPI-X4 è un derivato dell’albumina del siero umano precedentemente identificato dal team scientifico per inibire l’HIV. I ricercatori esamineranno nuovi derivati sintetici di EPI-X4 in modelli animali di malattie.
Obiettivo
Deregulation of CXCL12 signaling via the CXCR4 chemokine receptor plays a key role in many diseases, including cancer, rheumatoid arthritis, chronic inflammation and cardiovascular disorders. Thus, agents modulating CXCR4 signaling offer many prospects for therapeutic development. CXCR4 is also a major coreceptor for HIV entry. Thus, we used HIV as tool to screen peptide libraries encompassing the entire blood peptidome for novel CXCR4 ligands. This approach allowed the identification of a small fragment of human serum albumin as potent HIV inhibitor. Remarkably, this naturally occurring peptide, named EPI-X4 (Endogenous Peptide Inhibitor of CXCR4), blocks CXCL12/CXCR4 signaling and suppresses cancer cell migration and invasion. Preclinical studies in mice show that EPI-X4 mobilizes hematopoietic stem/progenitor cells and inhibits lung inflammation in an asthma model. Preliminary analyses suggest that EPI-X4 is more specific and better tolerated than Mozobiol® (AMD3100), the only CXCR4 antagonist approved for clinical application. Recently, we developed synthetic derivatives of EPI-X4 showing about three orders of magnitude improved potency against HIV as well as increased plasma stability. Key goals of this project are to determine the therapeutic potential of these improved derivatives against cancers (Aim 1) and inflammatory diseases (Aim 2) using established mouse models of colon carcinoma, osteosarcoma, glioblastoma, airway inflammation and dermatitis. These disorders were selected from the large number of CXCR4-linked diseases because no safe and effective treatment exists and since preclinical mouse models are available to determine whether EPI-X4 derived agents are more efficient and better tolerated than other compounds. In parallel to the experimental assessment of the therapeutic potential of these novel CXCR4 antagonists, we will perform market analyses and develop an IPR strategy to pave the way towards commercialization and future clinical application.
Campo scientifico
- medical and health scienceshealth sciencesinflammatory diseases
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugs
- natural sciencesbiological sciencesbiochemistrybiomolecules
- medical and health scienceshealth sciencesinfectious diseasesRNA virusesHIV
- medical and health sciencesclinical medicineoncology
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-POC - Proof of Concept GrantIstituzione ospitante
89081 Ulm
Germania