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

Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Currently treatment options for patients with PEL are limited. Oncolytic viruses have been engineered as anti-cancer agents and have recently shown increased therapeutic promise. Similarly, lytic activation of endogenous viruses from latently infected tumor cells can also be applied as a cancer therapy. In theory, such a therapeutic strategy would induce oncolysis by viral replication, while simultaneously stimulating an immune response to viral lytic cycle antigens. We examined the combination of the FDA-approved drug PEP005 (ingenol-3-angelate) with epigenetic drugs as a rational therapeutic approach for KSHV-mediated malignancies. JQ1, a bromodomain and extra terminal protein (BET) inhibitor, in combination with PEP005, not only robustly induced KSHV lytic replication, but also inhibited IL-6 production from PEL cells. Using the dosages of these agents that was found to be effective in reactivating HIV (as a means to clear latent virus with HAART 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 NF-B pathway <br />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.

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