Role of IKK epsilon in KSHV/HHV8 associated malignancies

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 DESCRIPTION (provided by applicant): Human herpesvirus 8 (HHV8), also known as Kaposi's sarcoma associated herpesvirus (KSHV) is the most frequent cause of malignancy among AIDS patients. In addition to Kaposi's sarcoma, infection with HHV8 has been linked to the occurrence of primary effusion lymphoma (PEL) or body cavity lymphoma. Due to underlying immunosuppression, KSHV-associated cancers have extremely poor prognosis when treated with conventional chemotherapy and there is urgent need for more effective and less toxic therapies for these disorders. We and others have previously reported that NF-κB pathway is constitutively active in HHV8-infected cells primarily due to the activity of HHV8-encoded vFLIP (viral FLICE inhibitory protein) K13, which activates this pathway by interacting with and activating a ~700 kDa IκB kinase (IKK) complex. We have discovered that inhibitors of IKKε (IKK epsilon), an IKK related kinase, are selectively toxic to cells that are dependent on K13-induced NF-κB for their survival. Additionally, IKKε is up-regulated by K13 and physically interacts with it. Since IKKε knockout mice, in contrast to IKKα or IKKβ knockout mice, are viable and fertile, our hypothesis is that IKKε may be a target of great clinical value for the treatment of KSHV associated PEL and KS. We plan to test this hypothesis through the following specific aims. In aim 1, we will delineate the role of IKKε in K13 and KSHV-induced NF-κB pathway. In aim 2, we will characterize the role of IKKε in the various biological activitis of K13 and KSHV. Finally, in aim 3, we will study the activity of IKKε inhibitors in KSHV-associated PEL and KS using in vitro and in vivo models. It is hoped that the above studies will not only clarify the role played by IKKε in K13- and KSHV- induced NF-κB but will also delineate its contribution to the pathogenesis of PEL of KS. Finally, these studies will lead to novel approaches for the treatment of PEL and KS.