Generation of an Oncolytic Adenovirus Targeting the CXCR4 and CXCR7 Chemokine Receptors in Breast Cancer

Breast cancer is the most diagnosed cancer in women under 60 and the second most diagnosed cancer in women over 60. While treatments for localized breast cancer are quite successful with high survival rates at 99%, advanced breast cancer remains hard to treat with a nearly 75% decrease in survival. Current treatments are inefficient at treating advanced stages of breast cancer, and thus, new therapies are sorely needed to address the complexity of advanced stage breast cancer. The ideal therapy would be capable of systemic administration, targets cancer cells and spares normal tissue. Oncolytic adenovirus is an ideal therapeutic vector due to its ease of manipulation, production and demonstrated clinical safety profile. In this study, we engineered an oncolytic adenovirus to target the chemokine receptors CXCR4 and CXCR7. The overexpression of CXCR4 and CXCR7 is implicated in the initiation, survival, progress and metastasis of breast cancer. Both receptors bind to the ligand, CXCL12 (SDF-1), which has been identified to play a crucial role in the metastasis of breast cancer cells. In this study we incorporated a T4-fiber fibritin protein fused to CXCL12 into the knob domain of an adenovirus to retarget the virus to the CXCR4 and CXCR7 receptors. We show that our modified virus targets and infects CXCR4 and CXCR7 overexpressing breast cancer cells more efficiently than a wild-type control. In addition, the substitution of the wild-type fiber and knob with our modified fiber and knob did not interfere with oncolytic capability. Overall, the results of this study set the foundation for future modifications or this vector and in vivo studies with the CXCL12 modified virus within immunocompetent animal models