Infection with the Kaposi's sarcoma associated herpesvirus (KSHV) 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. 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. Previous studies from our laboratory have shown that KSHV-encoded viral FLICE inhibitory protein (vFLIP) K13 is a powerful activator of the NF-kB pathway and plays a key role in the pathogenesis of KSHV-associated malignancies. K13 activates the NF-kB pathway by directly interacting with the NEMO/IKK3 subunit of the IkB kinase (IKK) complex and utilizes this pathway to promote cellular survival, proliferation, transformation and cytokine secretion. The above studies have established NF-kB pathway as an important therapeutic target for the treatment of KSHV-associated malignancies. However, since NF-kB pathway plays a key role in normal immune and inflammatory responses, global inhibitors of this pathway are likely to lead to severe immunosuppression, thus limiting their potential clinical utility in KSHV-infected patients. The overall goal of this proposal is to design cell-permeable helical peptides capable of blocking K13-NEMO interaction and to test their ability to block K13-induced NF-kB using in vitro and in vivo models developed in our laboratory. It is hoped that such peptides will specifically block K13-induced NF-kB without interfering with the physiological activation of this pathway during normal immune and inflammatory response.

Public Health Relevance

Kaposi's sarcoma associated herpesvirus (KSHV) is the commonest cause of malignancies among patients with AIDS. The goal of this project is to develop peptides that can block the activity of K13, a small protein encoded by KSHV. It is hoped that such peptides will have utility for the development of targeted therapies for KSHV-associated malignancies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019811-03
Application #
8236941
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2010-06-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$388,922
Indirect Cost
$148,847
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Tolani, B; Gopalakrishnan, R; Punj, V et al. (2014) Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors. Oncogene 33:2928-37
Tolani, Bhairavi; Matta, Hittu; Gopalakrishnan, Ramakrishnan et al. (2014) NEMO is essential for Kaposi's sarcoma-associated herpesvirus-encoded vFLIP K13-induced gene expression and protection against death receptor-induced cell death, and its N-terminal 251 residues are sufficient for this process. J Virol 88:6345-54
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
Gopalakrishnan, Ramakrishnan; Matta, Hittu; Chaudhary, Preet M (2013) A purine scaffold HSP90 inhibitor BIIB021 has selective activity against KSHV-associated primary effusion lymphoma and blocks vFLIP K13-induced NF-κB. Clin Cancer Res 19:5016-26
Matta, Hittu; Gopalakrishnan, Ramakrishnan; Graham, Ciaren et al. (2012) Kaposi's sarcoma associated herpesvirus encoded viral FLICE inhibitory protein K13 activates NF-ýýB pathway independent of TRAF6, TAK1 and LUBAC. PLoS One 7:e36601
Punj, Vasu; Matta, Hittu; Chaudhary, Preet M (2012) A computational profiling of changes in gene expression and transcription factors induced by vFLIP K13 in primary effusion lymphoma. PLoS One 7:e37498
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
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