Targeted Therapy for Burkitt Lymphoma in Resource Poor Settings

伯基特淋巴瘤（BL）在发展中国家特别常见，但与富裕国家发生的组织学相似的肿瘤不同。在美国发现的散发性和儿童BLs很少含有EBV，然而，非洲人群中的BLs与伽马疱疹病毒高度相关。我们的研究表明，EBV在淋巴瘤中的存在代表了一种选择性靶点，可以作为一种治疗形式加以利用。这些发现具有重要意义，并提示EBV相关的BLs应与病毒阴性肿瘤区别对待。大多数侵袭性或复发性B细胞淋巴瘤的新疗法都是基于强化化疗方案、昂贵的模式或实验性方法（基因治疗、细胞毒性T细胞输注），这些方法在资源匮乏的环境中难以实施，也不太可能适用于地方性或与艾滋病毒相关的B细胞淋巴瘤患者。我们已经证明，原发HIV/EBV相关的BLs对齐多夫定（AZT）介导的核因子κ B （NF-kB）和细胞凋亡的抑制敏感。在EBV淋巴瘤中抑制NF-kB具有独特而有效的双重抗肿瘤作用，通过阻断重要的生存因子和诱导EBV基因表达，包括病毒胸腺嘧啶激酶（vTK），其磷酸化胸腺嘧啶类似物AZT。我们的初步数据表明，一些原发的未经处理的伯基特淋巴瘤表达一种溶解成分，因此应该对AZT高度敏感。使用抗逆转录病毒药物AZT作为抗癌药物，对HIV和EBV相关淋巴瘤患者尤其可取。我们假设表达EBV I型潜伏期模式的BLs将通过破坏NF-kB对裂解诱导治疗特别敏感，而II型和III型潜伏膜蛋白1 （LMP-1）阳性肿瘤将需要更有效的转录因子抑制或诱导病毒裂解程序的药物应用。基于潜伏期、NF-kB表达和对病毒再激活敏感性的功能特性可能适用于EBV+BL。为了研究这一点，我们将研究原发性肿瘤的分子流行病学和发病机制，并对EBV+型BL患者衍生的淋巴瘤进行前瞻性分析。从这项临床前研究中获得的知识将对开发针对这些非常常见的肿瘤的靶向抗病毒治疗具有重要意义。我们已经在巴西建立了合作伙伴，以及出色的现场基础设施，这将促进这些研究。我们的长期目标是开发一种适用于发展中国家的EBV （HIV）相关淋巴瘤的靶向、有效、基于抗病毒的疗法。

Burkitt lymphoma (BL) is particularly common in developing countries but differs from histologically similar tumors that occur in affluent nations. Sporadic and pediatric BLs seen in the US rarely contain EBV however, BLs in African populations are highly associated with the gamma herpes virus. Our studies indicate that the presence of EBV in lymphomas represents a selective target that can be exploited as a form of therapy. These findings have important implications and suggest that EBV associated BLs should be treated differently from viral negative tumors. Most new therapies for aggressive or relapsed B cell lymphomas are based upon intensive chemotherapeutic regimens, expensive modalities or experimental approaches (gene therapy, cytotoxic T cell infusion) that are difficult to implement in resource poor settings and unlikely to be applicable in patients with the endemic or HIV associated forms of the disease. We have demonstrated that primary HIV/EBV associated BLs are susceptible to zidovudine (AZT) mediated inhibition of Nuclear Factor Kappa B (NF-kB) and apoptosis. Suppression of NF-kB in EBV lymphomas exerts a unique and potent dual anti-tumor effect by both blocking a vital survival factor and inducing the EBV gene expression including viral thymidine kinase (vTK), which phosphorylates the thymidine analogue, AZT. Our preliminary data indicates that some primary unmanipulated Burkitt lymphomas express a lytic component and therefore should be highly sensitive to AZT. The use of the antiretroviral AZT, as an anticancer agent, is particularly desirable in patients with HIV and EBV associated lymphoma. We hypothesize that BLs that express a Type I latency pattern of EBV will be uniquely sensitive to lytic induction therapy via disruption of NF-kB whereas Type II and III Latent Membrane Protein 1 (LMP-1) positive tumors will require more potent suppression of the transcription factor or application of agents that induce the viral lytic program. Functional properties based upon latency, NF-kB expression and sensitivity to viral reactivation may be applied to EBV+BL. In order to investigate this we will investigate the molecular epidemiology and pathogenesis of primary tumors and prospectively analyze lymphomas derived from patients with EBV+ forms of BL. Knowledge gained from this pre-clinical study will have significance towards the development of targeted antiviral based therapies for these very common tumors. We have established collaborators in Brazil as well as outstanding on site infrastructure that will facilitate these studies. Our long term goal is to develop a targeted, efficacious, antiviral-based therapy for EBV (HIV) associated lymphoma that is applicable in developing nations.