Table 2.
Current status of drugs targeting deregulated signaling pathways in angiosarcoma and other endothelial cell neoplasms
| Target | Drugs | Current development status |
|---|---|---|
| Angiogenesis | ||
| VEGF | Bevacizumab | Phase 2 trials with RR 9% (ref. 22) and 6 month PFS 54%, median OS 19.5 months;23 no benefit over paclitaxel alone |
| Aflibercept | No published studies to date | |
| VEGFR2 | Sorafenib | Phase II with RR 0–14%, median PFS of 2–5 months24–26 |
| Sunitinib | Case reports29, 30, 35 and 2 angiosarcoma patients in large Phase 2 trial31 | |
| Pazopanib | Case reports,27, 28 Phase 2 trial ongoing (NCT01462630) | |
| Cediranib, Axitinib, Ramucirumab | No published studies to date | |
| Tie2/Ang2 | Trebananib | Phase 2, no responses in 16 patients46 |
| Notch/DLL4 | Gamma-secretase inhibitors | GEM Notch KO models develop hepatic angiosarcomas,52, 53 no clinical studies in angiosarcoma; Preclinical studies with gamma-secretase inhibitors with activity against KS cell lines126 |
| FGF | Anti bFGF oligonucleotides | In vitro activity in KS132 |
| Sunitinib | See sunitinib above | |
| PDGF/PDGFR | Imatinib | Case reports59 |
| Dasatinib | In vitro activity in canine angiosarcoma57 | |
| Olaratumab | Phase II trial in soft tissue sarcoma, including angiosarcoma (NCT01185964) | |
| Angiostatin/endostatin | Angiostatin/endostatin | Case report,62 preclinical activity in hemangioendothelioma64 |
| CD105 (endoglin) | TRC0105 | Phase 1b/2a combined with pazopanib (NCT01975519) |
| Intracellular kinase and mTOR pathways | ||
| PLCG1 | No published inhibitors in clinical development | |
| Raf | Vemurafenib, dabrafenib | No published studies to date |
| MEK | Trametinib, cobimetinib | Preclinical activity in canine angiosarcoma with single agent and combined MEK and mTOR inhibition88 |
| mTOR | Everolimus, sirolimus, temsirolimus | Preclinical studies in angiosarcoma (see above); Case report in EHE;174 Tumor regression in transplant associated KS,128 phase I study in KS combined with HAART129 |
| Transcriptional control | ||
| MYC | BET inhibitors | Not currently being tested in vascular tumors |
| Beta-receptors | Propranolol | First-line therapy for IH;175–177 preclinical studies showed synergy in angiosarcoma and EHE cell lines178 |
| Glucocorticoid receptors | Prednisolone, methylprednisolone | First-line for hemangioendothelioma associated with Kasabach-Merritt syndrome179 |
| Prednisolone | RR 90% in IH146, 147 | |
| Prednisone | Similar response rate to propranolol in a phase 2 study for proliferating IH180 | |
VEGF vascular endothelial growth factor, RR response rate, PFS progression free survival, OS overall survival, VEGFR2 vascular endothelial growth factor receptor 2, Tie2 TEK tyrosine kinase, endothelial, Ang2 angiopoietin 2, DLL4 delta-like 4, KS Kaposi sarcoma, FGF fibroblast growth factor, PDGF/PDGFR platelet-derived growth factor/ platelet-derived growth factor receptor, CD105 endoglin; mTOR mammalian target of rapamycin, PLCG1 phospholipase C-gamma1, Raf Raf-1 proto-oncogene, MEK MAPK kinase, EHE epithelioid hemangioendothelioma, HAART highly active anti-retroviral therapy, MYC Myc proto-oncogene, BET bromodomain and extra-terminal domain family, IH infantile hemangioma