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Novel Variants of the Chemokine CXCL12 Inhibit Colorectal Carcinoma Metastasis

MCW #1548

 

 Key Inventor

Brian Volkman, PhD

 Background

Secondary tumor formation, through metastasis, is the leading cause of carcinoma-related death in the world. The role of chemokines in the directed migration of cancer cells from primary tumor to distal, alternative sites is well known. CXCL12 and its receptor CXCR4 are chemokines that are co-expressed in several tissues and cell types throughout the body and play essential roles in development. CXCL12 has a wide range of effects on CXCR4 expressing cells including the directed migration of leukocytes, lymphocytes and hematopoietic stem cells. This signaling axis is also an important regulator of directed carcinoma cell metastasis and a logical target for development of CXCR4-targeted cancer therapeutics.

 Description

NMR structural analysis of CXCL12 demonstrates the existence of a multi-state equilibrium of CXCL12 in which monomeric and dimeric CXCL12 interact differently with the N-terminal tail of CXCR4. Researchers at the Medical College of Wisconsin have designed a CXCL12 dimer (CXCL122), comprising two monomers that are linked together, that has promise as a therapeutic drug for treatment of cancer, inflammatory disorders, autoimmune disease and HIV/AIDS. Biochemical analysis which showed beta-arrestin 2 recruitment to CXCR4 upon stimulation with monomeric and recombinant CXCL12 was absent with CXCL122. In vitro data demonstrates that CXCL122 is a potent inhibitor of colorectal cancer migration. When tested in vivo, the addition of either monomeric, recombinant, or dimeric CXCL12 increased survival times while limiting hepatic metastases in mouse cecal wall xenografts with CXCL122 showing the broadest effective concentration range. These results illuminate a new approach for development of chemokine-based therapeutics in the treatment of metastatic cancers and demonstrate the importance of chemokine stoichiometry in regulating chemotactic migration by activating different combinations of signaling events.

 Features
  •  Novel composition of matter based on natural hormone
  •  Easily modified to increase stability and enhance pharmacokinetics
  •  Dose-dependently inhibits metastasis in vivo
  •  Broad-base therapeutic potential for a variety of metastatic cancers, autoimmune diseases and HIV/AIDS
 Stage of Development 

Pre-clinical data on colorectal cancer mouse model
 

 

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Summary Information

Patent Status:
  PCT/US09/35318

Mechanism of Action:
Inhibitor

Molecule Type:
Biologic

Patent Coverage Type:
Composition of Matter
Method of Use

Geographical Coverage:
US Patent
Worldwide Patent

Related Areas of Interest:
Autoimmune/Inflammation
Digestive System
Infections

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