Contents - College of Medical and Dental Sciences - University of ...
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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK<br />
Clinical & Epidemiology Abstract 50<br />
RAPAMYCIN IS EFFECTIVE AGAINST PTEN POSITIVE AIDS-DEFINING<br />
MALIGNANCIES<br />
Debasmita Roy, Sang-Hoon Sin, Ling Wang, Blossom A. Damania, Dirk P. Dittmer<br />
<strong>University</strong> <strong>of</strong> North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA<br />
Abstract<br />
Primary Effusion Lymphoma (PEL), a B-cell lymphoma characteristic <strong>of</strong> AIDS <strong>and</strong><br />
immune-compromised patients, is tightly correlated with Kaposi’s Sarcoma-associated<br />
Herpes Virus (KSHV) infection. In this study we investigate the effect <strong>of</strong> inhibition <strong>of</strong><br />
mTor signaling (mammalian target <strong>of</strong> Rapamycin) in PEL. The anti-tumor potential <strong>of</strong><br />
Rapamycin has been the subject <strong>of</strong> intense investigations <strong>and</strong> we have shown previously<br />
that it is effective against PEL both in culture <strong>and</strong> our murine xenograft model via downregulation<br />
<strong>of</strong> cytokines, IL-6 <strong>and</strong> IL-10 (Sin et. al. Blood 2007. 109(5)). Here we show<br />
that the PEL-specific inhibitory effect <strong>of</strong> Rapamycin is also mediated by reduction <strong>of</strong> proangiogenic<br />
Vascular Endothelial Growth Factor (VEGF). We further find that the genetic<br />
status <strong>of</strong> the mTOR signaling cascade is intact in PEL cells, without mutations in negative<br />
regulators such as Phosphatase <strong>and</strong> Tensin Homolog (PTEN), Tuberous Sclerosis (TSC)<br />
Factor-1 <strong>and</strong> TSC-2. Typically, Akt activation results from deletion <strong>of</strong> the PTEN gene<br />
resulting in hyperactivation <strong>of</strong> mTor; instead we observe that Akt is activated <strong>and</strong> PTEN<br />
inactivated post-translationally, presumably by viral factors. Specifically, we show the<br />
presence <strong>of</strong> wildtype PTEN, but that it is silenced epigenetically, the mechanism <strong>of</strong> which<br />
differs between PEL <strong>and</strong> KSHV-infected endothelial cells. This suggests that in the special<br />
case <strong>of</strong> HIV-AIDS defining malignancies, Rapamycin can be effective in PTEN wild type<br />
tumors, contrary to previous reports <strong>of</strong> Rapamycin being effective exclusively in PTEN<br />
deleted tumors.<br />
Presenting author Email: debasmita_roy@med.unc.edu<br />
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