CXCR4 in the Tumor Microenvironment

The field of immuno-oncology is rapidly evolving with recognition of the tumor microenvironment and its essential role in promoting tumor growth and suppressing immune surveillance. The tumor microenvironment includes non-cancerous fibroblasts, myeloid cells, immune cells, and secreted proteins that support the growth of the cancer.

The CXCR4 receptor and its ligand, CXCL12, are a receptor–ligand pair critically involved in the complex crosstalk between cancer cells and the microenvironment. The CXCR4/CXCL12 axis plays a fundamental role in establishing the immunosuppressive microenvironment and initiating the formation of new blood supply. CXCR4 is highly expressed in many cancer types, and its expression is a marker for poor prognosis.

 

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By blocking the binding of CXCL12 to CXCR4, our therapeutics are designed to halt the recruitment of key immune cells such as T-regulatory cells and myeloid derived suppressor cells (MDSCs), in and around the tumor. As a result, our therapeutics neutralize the immunosuppressive microenvironment and enable the cancer-fighting CD8+ T-cells to reach the tumor. In addition, our CXCR4 inhibitors block the formation of new vasculature, reducing the blood supply to growing tumors.

We believe that our CXCR4 inhibitors will have clinical benefit as monotherapy, and in combination with existing immunotherapy and targeted approaches. Proof-of-concept studies in animal models of cancer have demonstrated the benefits of CXCR4 antagonism as a component of cancer therapy. Pre-clinical studies have shown that CXCR4 inhibition has synergistic benefits with approved cancer treatments such as immunotherapies and targeted therapies.

Selected scientific references

  1. Duda DG Duda DG, Kozin SV, Kirkpatrick ND, Xu L, Fukumura D, Jain RK. CXCL12 (SDF1-α) -CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clinical Cancer Research (2011);17:2074–80.
  2. Fearon DT. The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunology Research (2014); 2(3): 187–193.
  3. Guo F, Wang Y, Liu J, Mok SC, Xue F, Zhang W. CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks. Oncogene (2015);1-11.

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