TABLE 1.
Potential new drugs for the treatment of KS
| Target | Biological effect | Agent | Proposed mechanism of action | Current status | Refs |
|---|---|---|---|---|---|
| VEGFC, VEGFD and VEGFR3 axis | Inhibits lymphangiogenesis | Cediranib (AZD2171) | Tyrosine kinase inhibitor blocking VEGFR3 | Phase II/III studies for various cancers, no clinical trials yet for KS | 176 |
| VEGFA | Inhibits angiogenesis | Bevacizumab, sorafenib, sunitinib and PTC299 | Monoclonal antibody bevacizumab that targets VEGF and small molecules that inhibit VEGFR (as well as KIT and PDGFR). PTC299 inhibits the production of VEGF by targeting post-transcriptional VEGF synthesis | NCI Phase II bevacizumab with liposomal doxorubicin; NCI Phase and PTC299 is in preclinical development | 177 |
| ANGPT2 | Inhibits angiogenesis and lymphangiogenesis | Blocks proliferation of KSHV-infected spindle cells that express ANGPT2 | Inhibitors in preclinical development | 41, 124, 178 | |
| DLL4 | Vascular disrupting | In preclinical studies, blocking of DLL4-NOTCH signalling results in a paradoxical increase in tumour vessel density, but causes marked growth inhibition owing to functionally defective vasculature | Inhibitors in preclinical development | 159, 160 | |
| NF-KB: vFLIP-IKKG | Inhibits inflammation, angiogenesis and cell proliferation | Small molecules currently being screened that could interfere with vFLIP-IKKG interaction | Preclinical development | 97, 98 | |
| KIT and PDGFR | Inhibits spindle cell proliferation | Imatinib | KIT and PDGFR implicated in KS cell proliferation | Phase I | 179, 180 |
| mTOR | Modulates immunity and inhibits cell proliferation | Sirolimus, tacrilimus and evirulumus | Small molecules that inhibit mTOR. KSHV infection activates mTOR signalling, which is important for cell survival and angiogenesis | Phase II/III studies | 132, 181 |
ANGPT2, angiopoietin 2; DLL4, delta-like ligand 4; IKKγ, inhibitor of κB kinase-γ; KSHV, Kaposi’s sarcoma herpesvirus; KS, Kaposi’s sarcoma; NCI, National Cancer Institutes; NF-κB, nuclear factor-κB; PDGFR, platelet-derived growth factor receptor; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; vFLIP, viral FLICE inhibitory protein.