Role of Arsenic Trioxide in Primary Effusion Lymphoma

人类疱疹病毒8（HHV 8），也称为卡波西肉瘤相关疱疹病毒（KSHV）是最常见的 艾滋病患者中常见的恶性肿瘤。HHV 8感染与 Kaposi肉瘤（KS）和几种淋巴增生性疾病，如原发性渗出性淋巴瘤 (PEL)多中心Castleman病和免疫母细胞/浆母细胞淋巴瘤。因为 潜在的免疫抑制，HHV 8相关的癌症在用 常规化疗和迫切需要更有效和毒性更小的治疗这些 紊乱然而，HHV 8在这些疾病的发病机制中的确切作用机制仍然是未知的。 不清楚我们已经发现K13，一种HHV 8编码的vFLIP（病毒FLICE抑制蛋白），具有 独特的能力，激活经典和替代NF-κ B途径，通过相互作用的不同 kB激酶（IKK）复合物的组成部分。我们进一步证明了K13是一种癌基因， 介导增加的细胞增殖、转化、细胞因子分泌和对生长的保护 因子撤除通过NF-κ B激活诱导凋亡。因此，我们认为K13是一个关键的球员， HHV 8相关淋巴增生性疾病的发病机制，是发展 分子靶向治疗我们进一步发现，三氧化二砷（As 2 O3），一种药物， 用于许多人类癌症的临床试验，是K13诱导的NF-κ B活性的有效抑制剂。主 本提案的目的是测试单独使用As 203对抗HHV-8相关恶性肿瘤的能力 并与其它药剂组合。我们计划通过以下具体目标实现这一目标。在aim中 1，我们将研究As 203阻断K13诱导的NF-κ B活化的机制。在目标2中，我们将研究 NF-κ B通路在As 203对PEL细胞的促凋亡和抗增殖活性中的作用。 最后，在目标3中，我们将研究As 203对HHV 8相关的体外和体内模型的作用。 恶性肿瘤。我们希望这些研究将导致开发出毒性更小、更有效的 用于治疗HHV 8相关淋巴增生性疾病的分子靶向药物。

Human herpes virus 8 (HHV8), also known as Kaposi's sarcoma associated herpes virus (KSHV) is the most frequent cause of malignancy among AIDS patients. Infection with HHV8 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. Because of underlying immunosuppression, HHV8-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. However, the exact mechanism of action of HHV8 in the pathogenesis of these disorders is still unclear. We have discovered that K13,an HHV8-encoded vFLIP (viral FLICE inhibitory protein), possesses the unique abilities to activate the classical and alternative NF-KB pathways by interacting with different components of the kB kinase (IKK) complex. We have further demonstrated that K13 is an oncogene which mediates increased cellular proliferation, transformation, cytokine secretion and protection against growth factor withdrawal-induced apoptosis via NF-KB activation. Thus, we believe that K13 is a pivotal player in the pathogenesis of HHV8-associated lymphoproliferative disorders and an ideal candidate for development of molecularly targeted therapies. We have further discovered that arsenic trioxide (As203), a drug which is in clinical trials for a number of human cancers, is a potent inhibitor of K13-induced NF-KB activity. The primary goal of this proposal is to test the ability of As203 against HHV-8 associated malignancies when used alone and in combination with other agents. We plan to achieve this goal through the following specific aims. In aim 1, we will study the mechanism by which As203 blocks K13-induced NF-KB activation. In aim 2, we will study the role of NF-KB pathway in the pro-apoptotic and anti-proliferative activities of As203 against PEL cells. Finally, in aim 3 we will study the effect of As203 on in vitro and in vivo models of HHV8-associated malignancies. We hope that these studies will lead to the development of less toxic and more effective molecularly targeted agents for the treatment of HHV8-associated lymphoproliferative disorders.