Targeted Therapy for Burkitt Lymphoma in Resource Poor Settings

资源匮乏地区伯基特淋巴瘤的靶向治疗

基本信息

项目摘要

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.
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科BL很少含有EBV,然而,非洲人群中的BL与γ疱疹病毒高度相关。 我们的研究表明,淋巴瘤中EBV的存在代表了一个选择性靶点,可以作为一种治疗形式加以利用。 这些发现具有重要意义,并表明EBV相关BL应与病毒阴性肿瘤不同治疗。 侵袭性或复发性B细胞淋巴瘤的大多数新疗法基于强化化疗方案、昂贵的方式或实验方法(基因疗法、细胞毒性T细胞输注),其难以在资源贫乏的环境中实施,并且不太可能适用于患有该疾病的地方性或HIV相关形式的患者。 我们已经证明,原发性HIV/EBV相关BL对齐多夫定(AZT)介导的核因子κ B(NF-kB)抑制和细胞凋亡敏感。 抑制EBV淋巴瘤中的NF-kB通过阻断重要的存活因子和诱导EBV基因表达(包括使胸苷类似物AZT磷酸化的病毒胸苷激酶(vTK))发挥独特且有效的双重抗肿瘤作用。 我们的初步数据表明,一些原发性未经处理的伯基特淋巴瘤表达裂解成分,因此应该是高度敏感的AZT。 抗逆转录病毒AZT作为抗癌剂的用途在患有HIV和EBV相关淋巴瘤的患者中是特别期望的。 我们假设,表达EBV I型潜伏模式的BL将对通过破坏NF-κ B的裂解诱导治疗唯一敏感,而II型和III型潜伏膜蛋白1(LMP-1)阳性肿瘤将需要更有效地抑制转录因子或应用诱导病毒裂解程序的药物。 基于潜伏期、NF-kB表达和对病毒再活化的敏感性的功能特性可应用于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,并前瞻性地分析来自EB病毒+型BL患者的淋巴瘤。 从这项临床前研究中获得的知识将对这些非常常见的肿瘤的靶向抗病毒治疗的发展具有重要意义。 我们在巴西建立了合作伙伴,并在现场建立了出色的基础设施,以促进这些研究。 我们的长期目标是开发一种适用于发展中国家的针对EBV(HIV)相关淋巴瘤的靶向、有效、基于抗病毒的治疗方法。

项目成果

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William J Harrington其他文献

The use of high-dose azidothymidine in combination with chemotherapy upfront is an effective treatment approach for gamma-herpes virus-related non-Hodgkin’s lymphomas
  • DOI:
    10.1186/1750-9378-5-s1-a81
  • 发表时间:
    2010-10-11
  • 期刊:
  • 影响因子:
    2.800
  • 作者:
    Ulas Darda Bayraktar;Eileen Bernal;Lisa Cabral;William J Harrington;Dirk P Dittmer;Juan Carlos Ramos
  • 通讯作者:
    Juan Carlos Ramos

William J Harrington的其他文献

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{{ truncateString('William J Harrington', 18)}}的其他基金

Targeting of EBV Latency in Burkitt's Lymphoma
伯基特淋巴瘤中 EBV 潜伏期的靶向治疗
  • 批准号:
    7289830
  • 财政年份:
    2006
  • 资助金额:
    $ 24.85万
  • 项目类别:
University of Miami
迈阿密大学
  • 批准号:
    7130723
  • 财政年份:
    2006
  • 资助金额:
    $ 24.85万
  • 项目类别:
Targeting of EBV Latency in Burkitt's Lymphoma
伯基特淋巴瘤中 EBV 潜伏期的靶向治疗
  • 批准号:
    7097879
  • 财政年份:
    2006
  • 资助金额:
    $ 24.85万
  • 项目类别:
Targeted Therapy for Burkitt Lymphoma in Resource Poor Settings
资源匮乏地区伯基特淋巴瘤的靶向治疗
  • 批准号:
    7121431
  • 财政年份:
    2006
  • 资助金额:
    $ 24.85万
  • 项目类别:
Viral Oncology Career Development Grant
病毒肿瘤学职业发展补助金
  • 批准号:
    6934666
  • 财政年份:
    2001
  • 资助金额:
    $ 24.85万
  • 项目类别:
Viral Oncology Career Development Grant
病毒肿瘤学职业发展补助金
  • 批准号:
    6649857
  • 财政年份:
    2001
  • 资助金额:
    $ 24.85万
  • 项目类别:
Viral Oncology Career Development Grant
病毒肿瘤学职业发展补助金
  • 批准号:
    6798179
  • 财政年份:
    2001
  • 资助金额:
    $ 24.85万
  • 项目类别:
Viral Oncology Career Development Grant
病毒肿瘤学职业发展补助金
  • 批准号:
    6522802
  • 财政年份:
    2001
  • 资助金额:
    $ 24.85万
  • 项目类别:
Viral Oncology Career Development Grant
病毒肿瘤学职业发展补助金
  • 批准号:
    6333297
  • 财政年份:
    2001
  • 资助金额:
    $ 24.85万
  • 项目类别:
Antiviral Mediated Apoptosis of Non-Hodgkin's Lymphoma
抗病毒介导的非霍奇金淋巴瘤细胞凋亡
  • 批准号:
    6734649
  • 财政年份:
    2000
  • 资助金额:
    $ 24.85万
  • 项目类别:

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