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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK Clinical & Epidemiology Abstract 49 HEIGHTENED REDOX STATUS OF PRIMARY EFFUSION LYMPHOMA CELLS CAN BE EXPLOITED THERAPEUTICALLY BY DECREASING RESISTANCE TO OXIDATIVE STRESS Darya Bubman 1 , Utthara Nayar 2 , Balasz Csernus 3 , Ilaria Guasparri 3 , Ethel Cesarman 3 1= Program in Pharmacology, Weill Cornell Graduate School of Medical Sciences, 2= Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, 3= Department of Pathology and Laboratory Medicine, Weill Cornell Medical College Abstract Intracellular reactive oxygen species (ROS) levels are maintained in a fine balance; high levels can induce an oxidative stress response and cell death, while chronic moderately high levels may promote neoplastic growth and proliferation. Specifically, a high level of the superoxide (O2 - ) species is associated with cellular transformation. We have shown that PEL cells have higher levels of ROS, particularly superoxide, than KSHV-negative cells. Furthermore, we showed that vFLIP is responsible for these high levels of superoxide, by both overexpression and knockdown approaches. PEL cells also express high levels of superoxide dismutases (SODs), specifically MnSOD, which is probably necessary for PEL cells to eliminate superoxide and avoid oxidative stress. We therefore determined whether oxidative stress could be used as an approach for the treatment of PEL. 2-Methoxyestradiol (2ME2), or Panzem (Entremed), is an endogenous metabolite of estrogen that has antiangiogenic and antitumor effects, and is currently in early clinical studies for a variety of neoplasms. While 2ME2 acts through multiple mechanisms of action, these include inhibition of SOD activity and disruption of angiogenesis through the inhibition of hypoxia inducible factor-1 alpha (HIF-1α), a protein required for angiogenesis and cell survival under hypoxic and oxidative stress. We therefore treated cells with 2ME2 in vitro, and demonstrated that PELs, but not normal lymphocytes, were extremely sensitive to drug. We also determined whether this drug is effective in vivo, by using a mouse PEL xenograft model with in vivo imaging, following oral administration of clinically formulated 2ME2. Presenting author Email: utn2001@med.cornell.edu 76
The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK Clinical & Epidemiology Abstract 50 RAPAMYCIN IS EFFECTIVE AGAINST PTEN POSITIVE AIDS-DEFINING MALIGNANCIES Debasmita Roy, Sang-Hoon Sin, Ling Wang, Blossom A. Damania, Dirk P. Dittmer University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Abstract Primary Effusion Lymphoma (PEL), a B-cell lymphoma characteristic of AIDS and immune-compromised patients, is tightly correlated with Kaposi’s Sarcoma-associated Herpes Virus (KSHV) infection. In this study we investigate the effect of inhibition of mTor signaling (mammalian target of Rapamycin) in PEL. The anti-tumor potential of Rapamycin has been the subject of intense investigations and we have shown previously that it is effective against PEL both in culture and our murine xenograft model via downregulation of cytokines, IL-6 and IL-10 (Sin et. al. Blood 2007. 109(5)). Here we show that the PEL-specific inhibitory effect of Rapamycin is also mediated by reduction of proangiogenic Vascular Endothelial Growth Factor (VEGF). We further find that the genetic status of the mTOR signaling cascade is intact in PEL cells, without mutations in negative regulators such as Phosphatase and Tensin Homolog (PTEN), Tuberous Sclerosis (TSC) Factor-1 and TSC-2. Typically, Akt activation results from deletion of the PTEN gene resulting in hyperactivation of mTor; instead we observe that Akt is activated and PTEN inactivated post-translationally, presumably by viral factors. Specifically, we show the presence of wildtype PTEN, but that it is silenced epigenetically, the mechanism of which differs between PEL and KSHV-infected endothelial cells. This suggests that in the special case of HIV-AIDS defining malignancies, Rapamycin can be effective in PTEN wild type tumors, contrary to previous reports of Rapamycin being effective exclusively in PTEN deleted tumors. Presenting author Email: debasmita_roy@med.unc.edu 77
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