The Robert H. Lurie Comprehensive Cancer Center

卡波西肉瘤相关疱疹病毒（KSHV）导致卡波西肉瘤（KS），这是最常见的艾滋病相关癌症。KS仍然知之甚少，缺乏有效的治疗策略，这在很大程度上是因为现有的实验模型没有捕捉到KSHV感染的KS肿瘤细胞的关键特征。KS肿瘤细胞可能是淋巴管内皮细胞（LEC）来源。我们已经建立了人原发性LEC的从头KSHV感染足以驱动KS肿瘤细胞标志的细胞增殖和接触抑制丧失的条件。我们已经生成了RNA-Seq数据集，描述了KS模型中KSHV诱导的基因表达变化。所得数据概括了KS的已知基因表达特征。更重要的是，这些数据还确定了KSHV转化的LEC与KS高度相关的新特征，包括几种癌症基因和药物靶点的失调。该提案的目的是使用我们新的KS模型和来自艾滋病癌症标本资源（ACSR）和其他来源的KS肿瘤来识别KS的药物驱动因素。该建议的中心假设是，KSHV介导的关键癌基因的上调和KSHV介导的关键肿瘤抑制基因（TSGs）的下调在KS中至关重要。我们进一步假设，这些癌症基因的表达失调可以用于治疗干预。为了验证我们的假设，我们提出了两个具体目标：在具体目标1中，我们将验证新的KSHV诱导的癌基因在我们的培养模型和KS肿瘤中的过表达，并测试这些癌基因对KSHV诱导的LEC增殖的重要性。在具体目标2中，我们将研究KSHV介导的KS中一个关键肿瘤抑制基因的抑制作用。拟议的研究是创新的，因为我们的主要LEC培养模型允许直接调查与KS相关的表型，并且因为所调查的癌症基因以前没有涉及KS。拟议的工作是显着的，因为结果预计将提供新的见解KS的机制。结果将是有影响力的，因为这项研究可以确定KS的新药物靶点。

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.