Human herpes virus 8 (HHV8), also known as Kaposi's sarcoma associated herpes virus (KSHV) is the most frequent cause of malignancy among AIDS patients. Infection with HHV8 has been linked to the occurrence of Kaposi's sarcoma (KS) and several lymphoproliferative disorders, such as primary effusion lymphoma (PEL), multicentric Castleman's disease and immunoblastic/plasmablastic lymphomas. Because of underlying immunosuppression, HHV8-associated cancers have extremely poor prognosis when treated with conventional chemotherapy and there is an urgent need for more effective and less toxic therapies for these disorders. However, the exact mechanism of action of HHV8 in the pathogenesis of these disorders is still unclear. We have discovered that K13, an HHV8-encoded vFLIP (viral FLICE inhibitory protein), possesses the unique abilities to activate the classical and alternative NF-KB pathways by interacting with different components of the IkB kinase (IKK) complex. We have further demonstrated that K13 is an oncogene which mediates increased cellular proliferation, transformation, cytokine secretion and protection against growth factor withdrawal-induced apoptosis via NF-KB activation. Thus, we believe that K13 is a pivotal player in the pathogenesis of HHV8-associated lymphoproliferative disorders and an ideal candidate for development of molecularly targeted therapies. We have further discovered that arsenic trioxide (As203), a drug which is in clinical trials for a number of human cancers, is a potent inhibitor of K13-induced NF-KB activity. The primary goal of this proposal is to test the ability of As203 against HHV-8 associated malignancies when used alone and in combination with other agents. We plan to achieve this goal through the following specific aims.
In aim 1, we will study the mechanism by which As203 blocks K13-induced NF-KB activation.
In aim 2, we will study the role of NF-KB pathway in the pro-apoptotic and anti-proliferative activities of As203 against PEL cells. Finally, in aim 3, we will study the effect of As203 on in vitro and in vivo models of HHV8-associated malignancies. We hope that these studies will lead to the development of less toxic and more effective molecularly targeted agents for the treatment of HHV8-associated lymphoproliferative disorders. ? ? ?
