Table 2.
Anti-angiogenic therapies in experimental models.
| Compound | Targets | Animal models | Study outcomes in animal models | Human disease | Study outcomes in human disease | Limitations | Ref. |
|---|---|---|---|---|---|---|---|
| Everolimus (Afinotor) | mTOR inhibitor | PCK rats Han:SPRD(Cy/+) rats |
Liver disease: prevention of liver cyst enlargement, reduction of fibrosis. Kidney disease: kidney cysts reduction at moderate dosage, amelioration of renal function loss. |
ADPKD | Kidney disease: decreased kidney volume but no recovery of renal function. | ADPKD animal models develop early and severe disease compared to humans and intervention is usually in early stage of disease. No studies were conducted in human PLD. In human studies decrease in kidney volume does not correlate with improvement in renal function. In human studies multiple side effects were reported. |
142,143 144 |
| SU5416 (Semaxanib) | VEGFR-2 selective inhibitor |
Conditional Pkd2KO mice Pkd2WS25/- |
Liver disease: Suppression of cholangiocyte proliferation, suppression of liver cyst growth Liver and kidney disease: prevention of liver cysts but not kidney cysts. |
n.a. | n.a. | n.a. | 7,145 |
| Rapamycin (Rapamune) | mTOR inhibitor | Conditional Pkd2KO mice | Suppression of cholangiocyte proliferation. Suppression of liver cyst growth. Suppression of fibrosis. Increased cholangiocyte apoptosis. |
PLD In ADPKD transplant |
Liver disease: reduction in polycystic liver volumes and a trend toward reduction in kidney volume. | The human study was retrospective | 6,146 |
| SQ22,536 | Adenylate cyclase 5 (AC5) inhibitor | Conditional Pkd2KO mice | Suppression of liver cyst growth | n.a. | n.a. | n.a. | 60 |
| Sorafenib (Nexavar) |
Multikinase inhibitor (Raf kinase, PDGF, VEGFR-2 VEGFR-3). Autophagy and apoptosis inducer. Ferroptosis activator. |
Partial portal vein ligation in rats. Common BDL in rats. |
Suppression of fibrosis. Suppression of portal pressure. |
Advanced or metastatic liver cancer and cirrhosis Clinical Trial: NCT00767468 |
No results reported | n.a. | 132 |
| anti-VEGFR1 mAb |
VEGFR-1 neutralising agents | CCl4 → mice | Suppression of fibrosis | n.a. | n.a. | n.a. | 147 |
| anti-VEGFR-2 mAb |
VEGFR-2 neutralising agents | CCl4 → mice | Suppression of angiogenesis | n.a. | n.a. | n.a. | 147 |
| SU11248 (Sunitinib) |
Multi-kinase inhibitor (VEGFR-2 PDGFRβ) |
CCl4 → rats | Suppression of fibrosis. Suppression of portal pressure. |
n.a. | n.a. | n.a. | 147 |
| Sec 5–27 | Secretin receptor inhibitor | dnTGF-βRII mice | Suppression of cholangiocyte proliferation. Suppression of angiogenesis. Suppression of fibrosis. Suppression of senescence. Reduction of inflammation. |
n.a. | n.a. | n.a. | 148 |
| ML221 | Apelin receptor (APJ) inhibitor | BDL → apelin-/- Mdr2-/- |
Suppression of cholangiocyte proliferation. Suppression of angiogenesis. Suppression of fibrosis. Suppression of senescence. Reduction of inflammation. |
n.a. | n.a. | n.a. | 149 |
| AG-012736 (Axitinib) | Selective second-generation VEGFRs inhibitor | Subcutaneous xenograft of human (NCC-BD1 and TKKK) CCA cell lines. | Growth inhibition of NCC-BD1 and TKKK. Decreased microvessel density. |
Hepatobiliary malignant tumours Clinical Trial: NCT04010071 |
-no results reported | n.a. | 150 |
ADPKD, autosomal dominant polycystic kidney disease; BDL, bile-duct ligation; CCA, cholangiocarcinoma; CCl4, carbon tetrachloride; mTOR, mammalian target of rapamycin; PDGF, platelet-derived growth factor; PDGFRβ, platelet-derived growth factor receptor-β; PLD, polycystic liver disease; TGF-βRII, transforming growth factor-β receptor 2; VEGF, vascular growth factor; VEGFR, vascular growth factor receptor.