Selective effects of oral antiangiogenic tyrosine kinase inhibitors on an animal model of hereditary hemorrhagic telangiectasia

• Published in: Journal of thrombosis and haemostasis 2017-06, Vol.15 (6), p.1095-1102
• Main Authors: Kim, Y. H., Kim, M.‐J., Choe, S.‐W., Sprecher, D., Lee, Y. J., P. Oh, S.
• Format: Article
• Language: English
• Subjects: Activin; activin receptors; Anemia; angiogenesis inhibitors; Animal models; Antibodies; arteriovenous malformation; Bleeding; Gastrointestinal tract; Hemoglobin; Hemorrhage; hereditary hemorrhagic; Hereditary hemorrhagic telangiectasia; Intestine; Oral administration; Skin; telangiectasia; Tyrosine kinase inhibitors; Vascular endothelial growth factor; Wounds
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.13683

Essentials Antiangiogenic drugs are indicated as therapies for hereditary hemorrhagic telangiectasia. We interrogated the response to four antiangiogenic drugs for anemia and intestinal bleeding. Sorafenib and a pazopanib analog significantly improved while erlotinib worsened anemia. Some oral antiangiogenic drugs were effective in reducing intestinal bleeding. Summary Background Epistaxis and gastrointestinal (GI) tract hemorrhages are common symptoms of aged hereditary hemorrhagic telangiectasia (HHT) patients that result in anemia. Clinical as well as animal studies have suggested that vascular endothelial growth factor (VEGF) neutralizing antibodies lessen hemorrhage associated with adult‐onset arteriovenous malformations (AVMs). Objectives The goal of this study is to evaluate potential therapeutic effects of oral delivery of four antiangiogenic tyrosine‐kinase inhibitors (TKIs) in the development of adult‐onset AVMs in a murine model of HHT. Methods An adult activin receptor‐like kinase 1 (Alk1)‐inducible knockout (iKO) model was utilized to evaluate the effect of oral administration of sorafenib, sunitinib, erlotinib and a pazopanib analog (GW771806) on hemoglobin level, GI hemorrhages and formation of wound‐induced skin AVMs. Results and Conclusions Sorafenib and GW771806 significantly improved, yet erlotinib worsened, anemia and GI‐bleeding in the Alk1‐iKO model. However, none of these TKIs appeared to be effective for inhibiting the development of wound‐induced skin AVMs. Taken together, these results suggest that oral delivery of antiangiogenic TKIs is selectively more effective for GI bleeding than mucocutaneous AVMs, and it may provide an experimental basis for selective therapeutic options depending on the symptoms of HHT.