Abstract 2456 For a Few Dollars More: Treatment of Metastatic Head and Neck Cancers with Dimerized CXCL12

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. As 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. However, novel treatments are being tested focusing on inhibiting defective regulatory proteins that, when overexpressed, stimulate cancerous cell production. One such protein is the CXC motif ligand 12 (CXCL12), also known as stromal cell-derived factor-1 (SDF-1), which is a chemokine ligand consisting of three stranded beta sheets followed by an alpha helix, stabilized by conserved cysteine residues forming typical two disulfide bonds. It plays a role in many physiological and pathological processes, such as cell chemotaxis. Normally, CXCL12 signals to its receptor, CXC chemokine receptor 4 (CXCR4), to regulate immune cell production and movement. However, in the setting of cancer, dysregulation of this signaling can result in aggressive cell movement and invasion, leading to metastasis of tumor cells, the activation of lymphocytes, and the progression and treatment resistance of cancers, including HNC. When CXCL12 and CXCR4 bind together, they release substances involved in the adhesion process, so tumor cells bind to endothelial cells. The degenerate tumor cells prevent their own death and continue to spread due to the activation of key signaling pathways. Therefore, novel treatments targeting the CXCL12-CXCR4 protein interaction may be beneficial in treating HNC. Recent studies conducted at the Medical College of Wisconsin suggest that dimerized forms of the CXCL12 protein inhibit its metastatic function in tumor models.