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

Cancer Gene Therapy volume 27, pages 356–367 (2020)Cite this article

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Abstract

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 × 1011 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.

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Acknowledgements

We thank Campus Animal Facilities, University of Guelph, for animal care services. We also thank Betty-Anne McBey for her technical assistance with this project and Jessica Minott for assistance with monitoring mice during the survival study.

Funding

Funding for this research was provided by grants from the Canadian Institutes of Health Research (JJP) and the Cancer Research Society (JJP and SKW) AAS was supported by a Vanier Canada Graduate Scholarship (CIHR) and a Brock Doctoral Scholarship; DLY was supported by an OVC PhD Scholarship. The project was also supported by a CAO Pilot grant from the Beth Israel Deaconess Medical Center (JL).

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Author notes

  1. These authors contributed equally: Darrick L. Yu, Ashley A. Stegelmeier

  2. These authors jointly supervised this work: Byram W. Bridle, James J. Petrik, Sarah K. Wootton

Authors and Affiliations

  1. Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada

    Darrick L. Yu, Ashley A. Stegelmeier, Natalie Chow, Amira D. Rghei, Byram W. Bridle & Sarah K. Wootton

  2. Department of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1, Canada

    Kathy Matuszewska & James J. Petrik

  3. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA

    Jack Lawler

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Correspondence to Byram W. Bridle, James J. Petrik or Sarah K. Wootton.

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Conflict of interest

JJP and JL are co-inventors on US patent US20140271641A1 for the treatment of ovarian cancer with 3TSR.

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All animal experiments were conducted in accordance with the Canadian Council on Animal Care guidelines and approved by the Animal Care Committee of the University of Guelph (AUP# 3827). 8-week-old C57BL/6 female mice were purchased from Charles River Laboratories (St. Constant, Quebec, Canada).

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Yu, D.L., Stegelmeier, A.A., Chow, N. et al. AAV-mediated expression of 3TSR inhibits tumor and metastatic lesion development and extends survival in a murine model of epithelial ovarian carcinoma. Cancer Gene Ther 27, 356–367 (2020). https://doi.org/10.1038/s41417-019-0108-8

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