AIDS related Kaposi's sarcoma displasy high expression of genes critical for vessel development including VEGF/VEGFRs; arterial-venous specification and maturation (Notch Receptor/ligands and EphrinB2/EphB4) KSHV latency and lytic cyle proteins profoundly regulate VEGF/Notch pathway. In addition KS tumor cells express endothelial precursor cell marker CD133 which is induced by Notch activation. Furthermore, Notch pathway also provides survival signal in KS cells through high expression of Notch ligand Dll4. Similarly EphrinB2 knock down in KS cells inhibits cell proliferation and induces apoptosis. Thus VEGF, Notch, EphrinB2 represent novel targets for KS therapy.
Inhibitors of Notch pathway including decoy soluble Dll4-Fc, and Dll4 neutralizing antibodies have been generated and tested in KS models in vitro and in vivo. Secondly, EphrinB2 inhibitor decoy soluble receptor EphB4 has been generated and tested in KS models in vitro and in vivo,
VEGF positively regulates Notch pathway which negatively regulates VEGF pathway. VEGF and Notch pathways positively regulate EphrinB2 which in turn positively regulates VEGF pathway. Thus targeted combination therapy has great potential to target both KS stem cells as well differentiated cells. Novel inhibitors and surrogate markers of activity should thus be tested in human trials.