Histiocytic sarcoma (HS) is an exceptionally rare malignant neoplasm derived from dendritic cells and histiocytes, with no available effective treatment options. Akt signaling and proteasome dysfunction have been implicated in the pathogenesis of the disease, both in humans and dogs. Our work aims to investigate the importance of the Akt signaling pathway and evaluate the potential of Akt-targeted therapy in a canine model of histiocytic sarcoma.
We demonstrated Akt signaling to be active in 9 out of 10 canine HS tumor samples, regardless the presence of PTEN. Moreover, the Akt signaling pathway appears to be constitutively active in DH82 cells — a cell line model of canine HS, when compared to control canine dendritic cells. Pharmacologic Akt inhibition resulted in significant decrease in Akt S473 phosphorylation, GSK-3β S9 phosphorylation, Akt activity, cell viability, increased apoptosis, and resulted in sensitization to proteasome inhibition-depended cell death in a synergistic manner. Proteasome inhibition using carfilzomib, an irreversible proteasome inhibitor, induced dose-depended/caspase-3 independent cell death, at clinically relevant drug concentrations. The therapeutic effect of Akt inhibition was validated in vivo using a DH82 xenograft murine model. Akt inhibition lead to reduced tumor growth, prolonged overall survival, and ameliorated splenomegaly, but not affected the lung metastasis. Moreover, the therapeutic effect of Akt inhibition was potentiated in combination with carfilzomib.
In conclusion, targeting Akt signaling may represent an attractive potential therapeutic target for the HS. Future studies are required to examine the clinical efficacy of Akt-targeted therapy in dogs with HS using novel selective Akt inhibitors. / Ph. D. / Histiocytic sarcoma (HS) is an exceptionally rare cancer of the immune system, with no effective treatment options available. Canine histiocytic sarcoma (cHS) is an aggressive tumor of the same cellular lineage, identified at increased relative frequency in specific dog breeds, with significant translational value. Akt signaling and proteasome dysfunction have been implicated in the pathogenesis of the disease, both in humans and dogs. Our study aims to investigate the importance of the Akt signaling pathway in the dog model of the disease and evaluate the potential of Akt-targeted therapy in a translational of histiocytic sarcoma. The work presented here demonstrates that Akt signaling appears aberrantly and constitutively activated in the canine model of HS. Importantly, Akt inhibition significantly reduced the tumor growth and prolonged the overall survival of the experimental animals. Moreover, Akt inhibition potentiated the anti-cancer activities of other anticancer drugs. Collectively, these findings provide an attractive therapeutic approach for the treatment of HS.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/97520 |
| Date | 12 October 2018 |
| Creators | Qin, Qizhi |
| Contributors | Biomedical and Veterinary Sciences, Dervisis, Nikolaos G., Davalos, Rafael V., Klahn, Shawna L., Allen, Irving C. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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