Role of Arsenic Trioxide in Primary Effusion Lymphoma

描述(申请人提供)：人类疱疹病毒8型(HHV8)，也被称为卡波西肉瘤相关疱疹病毒(KSHV)，是艾滋病患者最常见的恶性肿瘤原因。HHV8感染与卡波西氏肉瘤(KS)和几种淋巴增生性疾病的发生有关，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。由于潜在的免疫抑制，HHV8相关癌症在接受常规化疗时预后极差，迫切需要更有效和毒性更低的疗法来治疗这些疾病。然而，HHV8在这些疾病发病机制中的确切作用机制仍不清楚。我们发现，K13是一种HHV8编码的vFLIP(病毒FLICE抑制蛋白)，通过与IKB激酶(IKK)复合体的不同成分相互作用，具有激活经典和替代的NF-KB途径的独特能力。我们进一步证明，K13是一种癌基因，它通过激活核因子-KB，介导细胞增殖、转化、细胞因子分泌增加以及对生长因子停用诱导的细胞凋亡的保护作用。因此，我们认为K13在HHV8相关淋巴增生性疾病的发病机制中起关键作用，是开发分子靶向治疗的理想候选者。我们进一步发现，三氧化二砷(As203)是一种有效的抑制K13诱导的核因子-KB活性的药物，该药物正在对一些人类癌症进行临床试验。这项建议的主要目标是测试As203单独使用和与其他药物联合使用时对抗HHV-8相关恶性肿瘤的能力。我们计划通过以下具体目标实现这一目标。在目标1中，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活性中的作用。最后，在目标3中，我们将研究As203对HHV8相关恶性肿瘤体外和体内模型的影响。我们希望这些研究将导致低毒和更有效的分子靶向药物的开发，用于治疗HHV8相关的淋巴增生性疾病。

DESCRIPTION (provided by applicant): 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 an 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 IkB 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.