Abstract 2439 The Good, the Bad, and the Ugly of Chemokines: Inhibiting CXCR4 to Stop Metastasis of Head and Neck Cancers

Head and Neck Cancer (HNC) is a broad term used to refer to a wide array of malignant tumors that occur in the head and neck region. Being the seventh most common cancer worldwide, occurring more frequently in males than females, HNC is estimated to have caused over 15,000 deaths in the United States alone in 2022. Despite aggressive treatments with major surgery and/or high-dose radiotherapy to the head and neck, 5-year survival outcomes remain below 50% for advanced disease. Some causes of HNC include tobacco and alcohol use as well as Human Papilloma Virus. It is unknown why many HNC patients are resistant to traditional cancer treatments like chemotherapy and radiation. One possible explanation may be the abnormal expression of a specific protein receptor with treatment potential, CXC motif chemokine receptor 4 (CXCR4). Researchers at the Medical College of Wisconsin recently identified higher expression of CXCR4's ligand, CXC motif chemokine ligand 12 (CXCL12), in HNC tumor lines that exhibit resistance to radiotherapy (Zenga, 2022). CXCR4 consists of seven alpha helices that intertwine through the cell membrane and connect through intracellular loops exposed on both sides of the membrane. Normally, CXCL12-CXCR4 signaling serves to regulate immune cell production and movement. In the setting of cancer, dysregulation of CXCL12-CXCR4 signaling can result in aggressive cell movement and invasion, leading to metastasis of tumor cells, increased death risk, and the progression of cancer as it resists treatments. Therefore, novel treatments targeting the CXCL12-CXCR4 protein interaction may be beneficial in the treatment of HNC. Recent studies have suggested dimerized forms of the CXCL12 protein inhibit its metastatic function in tumor models (Drury, 2011). Our team has developed a three-dimensional structural model of the CXCR4 protein to better understand how its structure may regulate its ability to form dimers and interact with the CXCL12 ligand.