Oncolytic Reactivation of KSHV as a Therapeutic Approach for Primary Effusion Lymphoma

We examined the combination of the FDA-approved drug ingenol-3-angelate (PEP005) with epigenetic drugs as a rational therapeutic approach for KSHV-mediated malignancies. JQ1, a bromodomain and extra terminal (BET) protein inhibitor, in combination with PEP005, not only robustly induced KSHV lytic replication, but also inhibited IL6 production from PEL cells. Using the dosages of these agents that were found to be effective in reactivating HIV (as a means to clear latent virus with highly active antiretroviral therapy), we were able to inhibit PEL growth in vitro and delay tumor growth in a PEL xenograft tumor model. KSHV reactivation was mediated by activation of the NF-B pathway by PEP005, which led to increased occupancy of RNA polymerase II onto the KSHV genome. RNA-sequencing analysis further revealed cellular targets of PEP005, JQ1, and the synergistic effects of both. Thus, combination of PEP005 with a BET inhibitor may be considered as a rational therapeutic approach for the treatment of PEL. Mol Cancer Ther; 16(11); 2627–38. ©2017 AACR.

Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Zhou, F., Shimoda, M., Olney, L., Lyu, Y., Tran, K., Jiang, G., Nakano, K., Davis, R. R., Tepper, C. G., Maverakis, E., Campbell, M., Li, Y., Dandekar, S., Izumiya, Y. Tags: Models and Technologies Source Type: research