TITLE:
CXCL12 Retargeting of an Oncolytic Adenovirus Vector to the Chemokine CXCR4 and CXCR7 Receptors in Breast Cancer
AUTHORS:
Samia M. O’Bryan, J. Michael Mathis
KEYWORDS:
Adenovirus, Breast Cancer, Cancer, Chemokine, CXCL12, CXCR4, CXCR7, Oncolytic, Preclinical, Receptor, Virotherapy, Virus
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.12 No.6,
June
8,
2021
ABSTRACT: Breast
cancer is the most frequently diagnosed cancer in women under 60, and the
second most diagnosed cancer in women over 60. While significant progress has been made in developing targeted
therapies for breast cancer, advanced
breast cancer continues to have high mortality, with poor 5-year survival rates. Thus, current therapies are
insufficient in treating advanced stages of breast cancer; new
treatments are sorely needed to address the complexity of advanced-stage breast
cancer. Oncolytic virotherapy has been explored as a therapeutic approach
capable of systemic administration, targeting cancer cells, and sparing normal
tissue. In particular, oncolytic adenoviruses have been exploited as viral
vectors due to their 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. This study incorporated a T4 fibritin protein fused to CXCL12 into the
tail domain of an adenovirus fiber to
retarget the vector to the CXCR4 and CXCR7 chemokine receptors. We showed that the modified virus targets and infects
CXCR4- and CXCR7-overexpressing
breast cancer cells more efficiently than a wild-type control vector. In
addition, the substitution of the wild-type fiber and knob with the modified
chimeric fiber did not interfere with oncolytic capability. Overall, the
results of this study demonstrate the feasibility of retargeting adenovirus
vectors to chemokine receptor-positive tumors.