AAV-mediated expression of 3TSR inhibits tumor and metastatic lesion development and extends survival in a murine model of epithelial ovarian carcinoma

• Published in: Cancer gene therapy 2020-05, Vol.27 (5), p.356-367
• Main Authors: Yu, Darrick L., Stegelmeier, Ashley A., Chow, Natalie, Rghei, Amira D., Matuszewska, Kathy, Lawler, Jack, Bridle, Byram W., Petrik, James J., Wootton, Sarah K.
• Format: Article
• Language: English
• Subjects: 13/44; 631/67/2328; 64/60; 692/699/67/1517/1709; 96/106; 96/109; Animal models; Animals; Biomedical and Life Sciences; Biomedicine; Blood vessels; C-Terminus; Carcinoma, Ovarian Epithelial - genetics; Carcinoma, Ovarian Epithelial - mortality; Carcinoma, Ovarian Epithelial - secondary; Carcinoma, Ovarian Epithelial - therapy; Care and treatment; Cell Line, Tumor - transplantation; Chemotherapy; Cloning, Molecular; Disease Models, Animal; DNA viruses; Expression vectors; Female; Gene Expression; Gene Therapy; Genetic aspects; Genetic Therapy - methods; Genetic vectors; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Health aspects; HEK293 Cells; Humans; Injections, Intraperitoneal; Invasiveness; Metastases; Metastasis; Mice; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - genetics; Ovarian Neoplasms - mortality; Ovarian Neoplasms - pathology; Ovarian Neoplasms - therapy; Parvovirinae - genetics; Peptides; Prevention; Solid tumors; Survival; Thrombospondin; Thrombospondin 1 - genetics
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/s41417-019-0108-8

An integral step in the development of solid tumors is the recruitment of blood vessels to fuel tumor growth. Antiangiogenic therapies can inhibit this process and control solid tumor growth. Thrombospondin-1 is an antiangiogenic protein possessing three type I repeats (3TSR) near the center of the protein and a CD47-binding peptide (CD47) in its C-terminus. Previously, we showed that treatment with recombinant 3TSR induces tumor regression, normalizes tumor vasculature, and improves uptake of chemotherapy drugs in an orthotopic, syngeneic mouse model of advanced stage epithelial ovarian cancer (EOC). While effective, this intervention required daily intraperitoneal injections. To circumvent this, here we employ adeno-associated virus (AAV) gene therapy vectors to express 3TSR alone or in combination with the CD47-binding peptide of TSP-1 and evaluate the impact on tumor development and survival in a mouse model of EOC. A single intraperitoneal injection of 1 × 10 11  vg of AAV expressing 3TSR, CD47-binding peptide, or 3TSR + CD47 effectively suppressed primary tumor growth; however, only AAV-3TSR was able to inhibit development of secondary lesions at 90-days post-tumor implantation and significantly improve survival. Taken together, AAV-mediated expression of 3TSR appears safe and effective at inhibiting tumor development and represents a novel, less invasive approach for treating ovarian carcinoma.