Role of Arsenic Trioxide in Primary Effusion Lymphoma

人类疱疹病毒8型(HHV8)，又称卡波西氏肉瘤相关疱疹病毒(KSHV)，是目前感染人数最多的 爱滋病患者恶性肿瘤的常见原因。感染HHV8型病毒与这一事件有关 卡波西肉瘤(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. 在潜在的免疫抑制下，HHV8相关癌症在治疗时预后极差 常规化疗，迫切需要更有效、毒性更小的治疗方法。 精神错乱。然而，HHV8在这些疾病发病机制中的确切作用机制仍不清楚。 不清楚。我们发现，K13是一种HHV8编码的vFLIP(病毒FLICE抑制蛋白)，具有 通过与不同的基因相互作用激活经典和替代的核因子-kB通路的独特能力 KB激酶(Ikk)复合体的组成部分。我们进一步证明了K13是一种癌基因 促进细胞的增殖、转化、细胞因子的分泌和抑制生长 因子撤除通过激活核因子-kB诱导细胞凋亡。因此，我们认为K13是 HHV8相关淋巴增生性疾病的发病机制和发展的理想候选者 分子靶向疗法。我们还进一步发现，三氧化二砷(As203)是一种在 对一些人类癌症的临床试验，是一种有效的K13诱导的核因子-KB活性抑制物。初级阶段 这项建议的目标是测试单独使用As203对抗HHV-8相关恶性肿瘤的能力 并与其他药剂联合使用。我们计划通过以下具体目标实现这一目标。在AIM 1，我们将研究As203阻断K13诱导的NF-KB激活的机制。在目标2中，我们将研究 核因子-KB通路在As203抗PEL细胞促凋亡和抗增殖作用中的作用 最后，在目标3中，我们将研究As203对HHV8相关的体外和体内模型的影响 恶性肿瘤。我们希望这些研究将导致开发毒性更小和更有效的 治疗HHV8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.