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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA124621-01
Application #
7178982
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Liddell Huppi, Rebecca
Project Start
2006-12-01
Project End
2011-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
1
Fiscal Year
2007
Total Cost
$278,464
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Graham, Ciaren; Matta, Hittu; Yang, Yanqiang et al. (2013) Kaposi's sarcoma-associated herpesvirus oncoprotein K13 protects against B cell receptor-induced growth arrest and apoptosis through NF-ýýB activation. J Virol 87:2242-52
Yang, Yanqiang; Groshong, Jason S; Matta, Hittu et al. (2011) Constitutive NF-kappaB activation confers interleukin 6 (IL6) independence and resistance to dexamethasone and Janus kinase inhibitor INCB018424 in murine plasmacytoma cells. J Biol Chem 286:27988-97
Matta, Hittu; Gopalakrishnan, Ramakrishnan; Punj, Vasu et al. (2011) A20 is induced by Kaposi sarcoma-associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 and blocks K13-induced nuclear factor-kappaB in a negative feedback manner. J Biol Chem 286:21555-64
Punj, V; Matta, H; Schamus, S et al. (2010) Kaposi's sarcoma-associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 suppresses CXCR4 expression by upregulating miR-146a. Oncogene 29:1835-44
Punj, Vasu; Matta, Hittu; Schamus, Sandra et al. (2009) Induction of CCL20 production by Kaposi sarcoma-associated herpesvirus: role of viral FLICE inhibitory protein K13-induced NF-kappaB activation. Blood 113:5660-8
Matta, H; Punj, V; Schamus, S et al. (2008) A nuclear role for Kaposi's sarcoma-associated herpesvirus-encoded K13 protein in gene regulation. Oncogene 27:5243-53
Zhao, Jinshun; Punj, Vasu; Matta, Hittu et al. (2007) K13 blocks KSHV lytic replication and deregulates vIL6 and hIL6 expression: a model of lytic replication induced clonal selection in viral oncogenesis. PLoS One 2:e1067
Lacoste, Vincent; Nicot, Christophe; Gessain, Antoine et al. (2007) In primary effusion lymphoma cells, MYB transcriptional repression is associated with v-FLIP expression during latent KSHV infection while both v-FLIP and v-GPCR become involved during the lytic cycle. Br J Haematol 138:487-501