Inducing and targeting of EBV lytic antigens in lymphoma

淋巴瘤中EB病毒裂解抗原的诱导和靶向 EB病毒（EBV）阳性淋巴瘤包括移植后环境中的淋巴瘤、伯基特淋巴瘤（BL）、AIDS相关淋巴瘤（ARL）和某些形式的霍奇金、T细胞和自然杀伤（NK）细胞淋巴瘤。这些鼓室瘤是侵袭性恶性淋巴瘤，并且常常变得耐化疗。显然需要开发新的治疗方法。这项研究计划提出利用EBV病毒作为一种 特异性淋巴瘤靶点。 EBV是具有两个不同生命周期的疱疹病毒：导致新病毒体产生和释放的生产性“潜伏”周期和非生产性“潜伏”周期。大多数淋巴瘤细胞被潜伏的EBV感染，只有10种病毒以低水平表达。NF-kappaB在调节细胞的潜伏期和裂解性复制之间的转换中起着关键作用。 EB病毒发现蛋白酶体抑制剂通过抑制NF-κ B在体外从潜伏感染的细胞中重新激活潜伏的EBV。潜在的假设是蛋白酶体抑制剂Bortezaldehyde（Velcade TM）可用于启动EBV相关恶性肿瘤中的EBV裂解抗原表达，启动病毒TK和其他病毒抗原的表达，从而 使肿瘤细胞易于被核苷类似物更昔洛韦和免疫系统细胞杀死。 这种新的联合疗法将专门用于治疗EBV+淋巴瘤患者。 目标1：定义蛋白酶体抑制剂Bortezaline可以从EBV+淋巴瘤细胞中重新激活潜伏EBV并在细胞培养物和小鼠EBV+淋巴瘤异种移植模型中使这些细胞对Gancyclovir敏感的条件。 确定重新激活、间接杀伤和免疫应答对新治疗方法的贡献。 目标2：从资助期的第2年开始启动可行性研究，测试蛋白酶体抑制剂Bortezelatin与Gancyclovir联合治疗EBV* 淋巴瘤患者的安全性和有效性。确定 与治疗相关的分子事件。 总之，拟定的临床方案代表了从对EBV生物学的理解中获得的蛋白酶体抑制剂的新应用，旨在开发一种新型、毒性较小的EBV +淋巴瘤生物治疗方案。 正如他的简历清楚地表明，申请人致力于淋巴瘤领域的转化研究事业。这个为期3年的职业发展计划旨在促进所需的额外培训，并以可行性试验的形式将基础科学发现转化为临床。我们预计临床试验将取得成功，并计划在K23授权期后的时间内扩展到更大的多中心临床试验。

Inducing and targeting of EBV lytic antigens in lymphoma. Epstein-Barr Virus (EBV) positive lymphomas include lymphomas in the post-transplantation setting, Burkitt's lymphomas (BL), AIDS- related lymphomas (ARL), and some forms of Hodgkin, T-cell, and natural killer (NK) cell lymphomas. These tymphomas are aggressive malignant lymphomas and often become chemotherapy resistant. A clear need exists to develop novel therapeutic approaches. This research plan proposes to exploit the EBV virus as a specific lymphoma target. EBV is a herpesvirus with two different life cycles: the productive =tytic" cycle leading to the production and release of new virions and the non-productive "latent" cycle. Most lymphoma cells are infected with latent EBV, and only ten viral are expressed at low levels. NF-kappaB plays a critical role in regulating the switch between latency and lytic replication of EBV. Proteasome inhibitors, by inhibiting NF-kB were found to reactivate latent EBV from latently-infected cells in vitro. The underlying HYPOTHESIS is that the proteasome inhibitor Bortezomib (Velcade TM) can be used to initiate EBV lytic antigen expression in EBV-related malignancies, initiating the expression of viral TK and other viral antigens, thereby rendering the tumor cells susceptible to killing by the nucleoside analogue Gancyclovir and cells of the immune system. This novel combination therapy will be developed specifically for the treatment of patients with EBV+ lymphomas. AIM 1: Define the conditions by which proteasome inhibitor Bortezomib can reactivate latent EBV from EBV+ lymphoma cells and sensitize these cells to Gancyclovir in cell culture and a mouse EBV+ lymphoma -xenograft model. Determine the contribution of reactivation, by-standing killing and immune responses to the new therapeutic approach. AIM 2: Initiate a feasibility study beginning year 2 of the funding period, testing the safety and efficacy of the combination of proteasome inhibitor Bortezomib with Gancyclovir in patients with EBV* lymphomas. Determine the molecular events associated with the treatment. In summary, the proposed clinical protocol represents a novel application of proteasome inhibitors derived from the understanding of EBV biology, and aims to develop a novel, less toxic, biologic treatment protocol for EBV + lymphomas. As clearly demonstrated by his CV, the applicant has committed himself to a career in translational research in the field of lymphoma. This 3-year Career Development Plan aims to facilitate the required additional training and the translation of a basic science discovery to the clinic in form of a feasibility trial. We anticipate a successful clinical trial and plan the extension to a larger multi center clinical trial in the time following the K23 granting period.