O02 - Plasma Cytokeratin-18 Levels as Non-invasive Biomarker of Early Gastrointestinal Toxicity in Dogs Receiving Toceranib
Thursday, June 14
1:45 PM - 2:00 PM
Location: WSCC 615
Research Abstract - Oral Presenter(s)
Toceranib phosphate is a tyrosine kinase inhibitor (TKI) frequently used in veterinary medicine for treatment of a number of tumor types. Despite studies demonstrating that lower doses of toceranib (2.4 - 2.9 mg/kg every other day) provides drug exposure sufficient for target inhibition while reducing the frequency of drug-related adverse events, gastrointestinal (GI) toxicity continues to be the most commonly encountered side effect in dogs receiving toceranib at this dose. The degree of toxicity is variable among individual dogs and currently there are no clinical or molecular markers to identify those dogs that would benefit from the use of concomitant medications to prevent GI toxicities. This is critical as the development of GI toxicity significantly impacts patient morbidity and quality of life, decreases treatment intensity, increases the cost of treatment, and leads to discontinuation of therapy.
Cytokeratin 18 (CK18) is a member of the intermediate filament family of cytoskeletal proteins and is highly expressed in epithelial cells, notably gastrointestinal mucosal epithelium. Epithelial cells undergoing necrosis and/or apoptosis release full-length or caspase-cleaved CK18 fragments that are detectable in bodily fluids such as serum and plasma. In humans, circulating levels of CK18 have been shown to have potential clinical utility as non-invasive prognostic or predictive biomarkers in a number of solid and hematopoietic tumor types. Data from human lymphoma studies indicate that serum CK18 levels increase following cytotoxic chemotherapy and that high CK18 expression correlates with patients experiencing epithelial toxicity, suggesting that circulating CK18 may have potential utility as predictive biomarker for early gastrointestinal toxicity. Given the lack of clinically relevant biomarkers for the early detection of GI toxicity in veterinary patients receiving anti-cancer drugs, the objective of our study was to determine plasma CK18 levels in dogs with cutaneous and subcutaneous mast cell tumors (MCTs) receiving single-agent toceranib therapy as a reference for understanding the relevance of any changes for the detection of early GI toxicity.
Blood was collected from 20 healthy dogs > 1 year of age with no medical history of gastrointestinal disease or recent gastrointestinal signs including vomiting and diarrhea, to establish a reference range for plasma CK18 levels in healthy control animals. Twenty five client-owned dogs with a histopathological diagnosis of cutaneous or subcutaneous MCTs and no evidence of gross and/or metastatic disease at the time of evaluation were enrolled. Patients were treated with toceranib (2.75 mg/kg EOD) and received Omeprazole (1 mg/kg SID). No dogs received concurrent prednisone and/or other concomitant medications. Plasma was collected from treatment dogs at day 0, day 7, day 14, day 21, and day 28.Clients were instructed to record any gastrointestinal or other clinical signs over the 28 day period. Drug-related adverse events (AEs) were defined and graded according to the published VCOG-CTCAE criteria. Plasma CK18 measurements were obtained for control dogs and treated dogs at all study timepoints using a commercially available canine enzyme-linked immunosorbent assay (ELISA) kit to detect CK18 (NeoBiolab). Determination of plasma VEGF concentrations in treated dogs was performed at all timepoints using a canine VEGF Quantikine ELISA kit (R & D Systems) as a surrogate biomarker of pathway inhibition by toceranib. Preliminary data indicate that baseline plasma CK18 levels are increased in dogs with a diagnosis of cutaneous or subcutaneous MCT compared to healthy control animals. Interestingly, while baseline CK18 levels were elevated in treated dogs, we observed a decline in CK18 levels over the period of the study with plasma CK18 concentrations appearing to plateau over days 14 to 21. No changes in plasma CK18 were correlated with toceranib-related adverse effects and/or grade. However, of the dogs experiencing gastrointestinal toxicity, most were mild. 14 dogs experienced a grade I gastrointestinal toxicity. 7 experienced a grade II toxicity, while only 1 experienced a grade III toxicity. No patients experienced a grade IV or greater gastrointestinal toxicity during the study. Despite the small number of subjects assessed in the current study, these data suggest that plasma CK18 is not a suitable biomarker for the early detection of toceranib-related gastrointestinal toxicity in dogs. However, further investigations to fully assess the predictive value of circulating CK18 detecting early GI toxicity in a larger cohort of patients is required.