Abstract
While extremely rare in humans, hemangiosarcoma (HSA) accounts for nearly 2% of canine neoplasia, and is characterized by both aggressive local growth/invasion and a high rate of metastasis. Both canine and human HSA exhibit sustained aberrant PI3K/Akt/mTOR pathway signaling. The purpose of this study was to examine the in vitro effects of a novel dual PI3K/mTOR inhibitor, VDC-597, in three canine HSA cell lines (DEN-, CIN-, and SB-HSA). VDC-597 suppressed activation of both Akt and 4eBP1 in canine HSA cells in a dose-dependent fashion, with an IC50 of approximately 0.3 uM, a concentration predicted to be clinically achievable based on preliminary early-phase canine and human studies. VDC-597 dose-dependently reduced proliferation, migration, and vascular endothelial growth factor production in HSA cells, while promoting tumor cell apoptosis. VDC-597 demonstrated additive antiproliferative effects when combined with doxorubicin. These results suggest that inhibitors of the PI3K/mTOR pathway may act against multiple components of the neoplastic process, including proliferation/apoptosis, chemosensitivity, migration, and angiogenesis, and justify the evaluation of PI3K/mTOR inhibitors in canine, and potentially human, HSA.
Highlights
Canine hemangiosarcoma (HSA) is an aggressive neoplasm derived from endothelial cells or hematopoietic precursors that accounts for nearly 2% of all cancer diagnosed in dogs [1, 2]
We found that inhibition of this pathway decreased cell proliferation, increased apoptosis, decreased the ability of HSA cells to migrate and invade, and reduced vascular endothelial growth factor (VEGF) production
While surgery to remove the primary tumor is the initial treatment of choice, the median survival time (MST) with surgery alone is only approximately 2 months [23]
Summary
Canine hemangiosarcoma (HSA) is an aggressive neoplasm derived from endothelial cells or hematopoietic precursors that accounts for nearly 2% of all cancer diagnosed in dogs [1, 2]. The most common sites of involvement are the spleen, skin and subcutaneous tissues, and the heart [3]. Current standard of care treatment involves surgical resection (if possible) followed by doxorubicin (DOX)-based chemotherapy. Regardless of the treatment protocol, the median postsurgical survival time for dogs with visceral HSA is less than 6 months [4]. The PI3K/mTOR pathway is intimately associated with cell survival, proliferation, apoptosis, and cytoskeletal rearrangement. Activation of this pathway generally occurs through initial
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