The Robert H. Lurie Comprehensive Cancer Center

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Kaposi’s sarcoma-associated herpesvirus (KSHV) causes Kaposi’s Sarcoma (KS), the most common AIDSassociated cancer. KS remains poorly understood and effective treatment strategies are lacking, in large part because available experimental models do not capture key features of the KSHV-infected KS tumor cells. KS tumor cells are of likely lymphatic endothelial cell (LEC) origin. We have established conditions where the de novo KSHV infection of human primary LEC is sufficient to drive the cellular proliferation and loss of contact inhibition that are hallmarks of KS tumor cells. We have generated RNA-Seq datasets that describe KSHV-induced gene expression changes in this KS model. Resulting data recapitulate known gene expression features of KS. More importantly, these data additionally identify novel features of KSHVtransformed LEC with high relevance to KS, including deregulation of several cancer genes and drug targets. The objective of this proposal is to use our new KS model and KS tumors from the AIDS Cancer Specimen Resource (ACSR) and other sources to identify druggable drivers of KS. The central hypothesis of this proposal is that KSHV-mediated upregulation of key oncogenes and KSHV-mediated downregulation of key tumor suppressor genes (TSGs) are critical in KS. We further hypothesize that the deregulated expression of these cancer genes can be exploited for therapeutic intervention. To test our hypothesis, we propose two Specific Aims: In Specific Aim 1, we will validate the overexpression of novel KSHV-induced oncogenes in our culture model and in KS tumors and test the importance of these oncogenes for KSHV-induced LEC proliferation. In Specific Aim 2, we will investigate the role of the KSHV-mediated repression of a key tumor suppressor gene in KS. The proposed study is innovative, because our primary LEC culture model allows straight-forward investigation of phenotypes with relevance to KS and because the investigated cancer genes have not previously been implicated in KS. The proposed work is significant, because results are expected to give new insights into the mechanisms underlying KS. Results will be impactful, because this study could identify new drug targets in KS.