New Therapeutics for Post-Transplant Lymphoproliferative Disorder

移植后淋巴增殖性疾病的新疗法

• 批准号: 9277357
• 负责人: Olivia M Martinez
• 金额: $ 39.81万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277357
• 关键词: Accounting; Address; Affect; Allografting; Antibodies; Apoptosis; B-Cell Lymphomas; B-Lymphocytes; BIRC4 gene; Biochemical; Biology; Bone Marrow Transplantation; Cardiac; Cardiovascular system; Cause of Death; Cell Survival; Cells; Clinical Trials; Complication; Consensus; Data; Disease; Epstein-Barr Virus Infections; Epstein-Barr pathogenesis; FRAP1 gene; Genes; Goals; Graft Rejection; Graft Survival; Growth; Growth Factor; Heart Transplantation; Human Herpesvirus 4; Immune response; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Infection; Interleukin-10; Laboratories; Lymphoma; Lymphomagenesis; Lymphoproliferative Disorders; Malignant Neoplasms; Membrane Proteins; MicroRNAs; Modeling; Molecular; Mus; Oncogenes; Organ; Organ Transplantation; Outcome; Pathogenesis; Pathway interactions; Patients; Play; Predisposition; Production; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; Radiation therapy; Regulation; Relapse; Role; Series; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Solid; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; Transplant Recipients; Transplantation; Viral Pathogenesis; Viral Proteins; Work; autocrine; chemotherapy; effective therapy; end stage disease; genetic regulatory protein; improved; in vivo; individual patient; infected B cell; inhibitor/antagonist; mortality; mouse model; new therapeutic target; novel; novel therapeutics; prevent; rituximab; small molecule inhibitor; success; therapeutic target; treatment strategy

7. PROJECT SUMMARY/ABSTRACT While the use of immunosuppression is crucial to the success of solid organ transplantation, it also predisposes patients to an increased incidence of infection and malignancy. Epstein Barr virus (EBV) B cell lymphomas associated with post-transplant lymphoproliferative disorder (PTLD) represent one of the most challenging, and serious, complications in transplant recipients. Currently, there is no consensus on treatment strategies for patients with PTLD, in part because the approaches utilized vary in their efficacy and because we cannot predict which therapy will best benefit a given patient. Furthermore, relapse and treatment-related mortality are major concerns. Our laboratory has worked to elucidate the underlying pathogenesis of EBV+ PTLD as a strategy to identify novel therapeutic targets. We have discovered that the PI3K/Akt/mTOR pathway is constitutively active in EBV+ B cell lymphomas from patients with PTLD and that EBV contributes to dysregulation of this pathway. We have also shown that survival and proliferation of EBV+ B cell lymphomas depends upon the PI3K/Akt/mTOR pathway because small molecule inhibitors, or siRNA, that target pathway constituents significantly inhibit lymphoma growth. In this proposal we will 1) determine the role of the PI3K/Akt/mTOR pathway in survival and growth of EBV+ B cell lymphomas, and apply rational therapeutics for targeting key nodes in the pathway; 2) define the mechanisms underlying PI3K/Akt/mTOR dysregulation in EBV+ B cell lymphomas and 3) determine if targeting the PI3K/Akt/mTOR pathway prolongs graft survival and can simultaneously inhibit lymphoma growth. To accomplish Aim 1 we will target mTOR in combination with PI3K or Akt proteins in EBV+ B cell lymphomas, both in vitro and in a mouse model of PTLD, to exploit our biochemical studies that revealed dysregulation of PI3K/Akt/mTOR is a common feature of EBV+ B cell lymphomas. In Aim 2 we will determine whether deficiencies in negative regulatory proteins plays a role in constitutive signaling of the PI3K/Akt/mTOR pathway in EBV+ B cell lymphomas. We will also evaluate how diversity in the LMP1 gene affects pathway activation and assess whether LMP1 coopts the host cell microRNA network to undermine regulation of PI3K/Akt/mTOR in infected B cells. In Aim 3 we characterize the effect of PI3K/Akt/mTOR small molecule inhibitors on alloactivation of T cells and graft survival. We also utilize an LMP1 transgenic mouse model to investigate how modulation of specific nodes in the PI3K/Akt/mTOR pathway alters B cell lymphoma growth in transplant recipients. These studies will create new opportunities for improving the treatment of EBV+ PTLD, and will also increase our basic understanding of EBV+ B cell lymphoma biology and the immune response to the allograft.

7.项目摘要/摘要 虽然免疫抑制的使用对实体器官移植的成功至关重要，但它也 使患者易患感染和恶性肿瘤的几率增加。EB病毒B细胞 与移植后淋巴增生性疾病(PTLD)相关的淋巴瘤是最常见的 移植受者的并发症具有挑战性，也很严重。目前，在治疗方面还没有达成共识。 对于PTLD患者的策略，部分原因是所采用的方法在疗效上有所不同，而且因为我们 无法预测哪种疗法对特定患者最有利。此外，复发和治疗相关 死亡率是人们主要关注的问题。我们的实验室致力于阐明EBV+的潜在发病机制 PTLD作为一种确定新治疗靶点的策略。我们发现PI3K/Akt/mTOR 途径在PTLD患者的EBV+B细胞淋巴瘤中是结构性活跃的，并且EBV参与了 这条通路的失调。我们还表明，EBV+B细胞淋巴瘤的存活和增殖 依赖于PI3K/Akt/mTOR途径，因为小分子抑制物或siRNA，即靶向途径 成分显著抑制淋巴瘤的生长。在本提案中，我们将1)确定 PI3K/Akt/mTOR通路在EBV+B细胞淋巴瘤生存和生长中的作用 2)确定PI3K/Akt/mTOR异常调控的机制。 EBV+B细胞淋巴瘤和3)确定靶向PI3K/Akt/mTOR通路是否延长移植物存活和 可以同时抑制淋巴瘤的生长。为了实现目标1，我们将把mTOR目标与 在体外和PTLD小鼠模型中，EBV+B细胞淋巴瘤中的PI3K或Akt蛋白，以开发我们的 生化研究发现PI3K/Akt/mTOR异常是EBV+B细胞的共同特征 淋巴瘤。在目标2中，我们将确定负调控蛋白的缺陷是否在 EBV+B细胞淋巴瘤中PI3K/Akt/mTOR信号通路的组成信号我们还将评估如何 LMP1基因的多样性影响途径激活，并评估LMP1是否选择宿主细胞 MicroRNA网络破坏感染B细胞中PI3K/Akt/mTOR的调节。在目标3中，我们描述了 PI3K/Akt/mTOR小分子抑制剂对T细胞同种异体活化和移植物存活的影响我们还利用 LMP1转基因小鼠模型研究PI3K/Akt/mTOR中特定节点的调控 途径改变移植受者的B细胞淋巴瘤生长。这些研究将创造新的机会 对于提高EBV+PTLD的治疗水平，也将增加我们对EBV+B细胞的基本认识 淋巴瘤生物学和对同种异体移植的免疫反应。