The receptor tyrosine kinase AXL is thought to play a role in metastasis, but the therapeutic efficacy of an AXL targeting agent remains largely untested in metastatic disease. In this study, we defined AXL as a therapeutic target for metastatic ovarian cancer. AXL is primarily expressed in metastases and advanced stage human ovarian tumors but not in normal ovarian epithelium. Genetic inhibition of AXL in human metastatic ovarian tumor cells is sufficient to prevent the initiation of metastatic disease in vivo. Mechanistically, inhibition of AXL signaling in animals with metastatic disease results in decreased invasion and MMP activity. Most importantly, soluble human AXL receptors that imposed a specific blockade of the GAS6/AXL pathway had a profound inhibitory effect on progression of established metastatic ovarian cancer without normal tissue toxicity. These results offer the first genetic validation of GAS6/AXL targeting as an effective strategy for inhibition of metastatic tumor progression in vivo. Furthermore, this study defines soluble AXL receptor therapy as a therapeutic candidate agent treating metastatic ovarian cancer, where current therapies are ineffective.

BackgroundGastrointestinal stromal tumors (GISTs) are uncommon intestinal neoplasms in the dog. Literature regarding adjunctive therapy for GISTs in dogs is sparse. High‐risk GISTs in humans respond to tyrosine kinase inhibition in the adjuvant setting.ObjectivesTo review cases of toceranib phosphate use in dogs with GISTs and provide initial assessment of possible biological activity. A secondary aim was to evaluate patient and tumor characteristics for possible prognostic value.AnimalsTwenty‐seven dogs with confirmed GISTs based on histopathology and immunohistochemistry treated with toceranib.MethodsRetrospective study in which cases of toceranib use in dogs with GIST were solicited using the American College of Veterinary Internal Medicine Oncology and Small Animal Internal Medicine listservs.ResultsFive of 7 dogs with gross disease experienced clinical benefit (71%; 3 complete responses, 1 partial response, 1 stable disease). These included 2 dogs with durable responses after toceranib discontinuation. Median progression‐free interval (PFI) in dogs with gross disease was 110 weeks (range, 36‐155 weeks). Median PFI in dogs with microscopic disease was 67 weeks (range, 9‐257 weeks). Metastasis at diagnosis (P = 0.04) and high mitotic index (P < 0.001) were associated with shorter PFI in toceranib‐treated dogs.Conclusions and Clinical ImportanceBiological activity of toceranib is evident in dogs with gross disease. Metastasis of GIST at diagnosis, as well as high tumor mitotic index, was associated with shorter PFI in toceranib‐treated dogs. Larger studies are needed to define postsurgical risk and refine the use of toceranib in dogs with gross and microscopic GIST.