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Therapeutic potential of optimized derivatives of an endogenous CXCR4 antagonist for the treatment of cancers and inflammatory diseases

Project description

Novel drugs against cancer and inflammatory diseases

CXCR4 is a chemokine receptor implicated in several pathological conditions including cancer and viral infections. It is activated by CXCL12, which regulates cell adhesion to stroma and hematopoietic stem cell mobilisation, and also serves as a co-receptor for HIV entry into cells. The aim of the EU-funded EPI-X4Health project is to test the endogenous peptide EPI-X4 for its therapeutic potential against cancer and inflammatory diseases. EPI-X4 is a human serum albumin derivative previously identified by the scientific team to inhibit HIV. Researchers will screen new synthetic derivatives of EPI-X4 in animal models of disease.

Objective

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.

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Coordinator

UNIVERSITAET ULM
Net EU contribution
€ 95 256,00
Address
Helmholtzstrasse 16
89081 Ulm
Germany

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Region
Baden-Württemberg Tübingen Ulm, Stadtkreis
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00

Beneficiaries (3)