New Therapeutics for Post-Transplant Lymphoproliferative Disorder

移植后淋巴增殖性疾病的新疗法

基本信息

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
项目类别：
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

项目摘要

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. 项目概要/摘要虽然免疫抑制剂的使用对于实体器官移植的成功至关重要，但它也使患者感染和恶性肿瘤的发生率增加。 EB 病毒 (EBV) B 细胞与移植后淋巴增殖性疾病（PTLD）相关的淋巴瘤是最常见的淋巴瘤之一移植受者面临的具有挑战性且严重的并发症。目前治疗尚未达成共识 PTLD 患者的治疗策略，部分原因是所采用的方法的疗效各不相同，而且我们无法预测哪种疗法最有利于特定患者。此外，复发和治疗相关死亡率是主要问题。我们的实验室致力于阐明 EBV+ 的潜在发病机制 PTLD 作为识别新治疗靶点的策略。我们发现 PI3K/Akt/mTOR 该途径在 PTLD 患者的 EBV+ B 细胞淋巴瘤中持续活跃，并且 EBV 有助于该通路的失调。我们还表明 EBV+ B 细胞淋巴瘤的存活和增殖取决于 PI3K/Akt/mTOR 通路，因为小分子抑制剂 (siRNA) 靶向通路成分显着抑制淋巴瘤生长。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，并应用合理的治疗方法针对路径中的关键节点； 2) 定义 PI3K/Akt/mTOR 失调的机制 EBV+ B 细胞淋巴瘤和 3) 确定靶向 PI3K/Akt/mTOR 通路是否可以延长移植物存活和同时可以抑制淋巴瘤的生长。为了实现目标 1，我们将结合 mTOR EBV+ B 细胞淋巴瘤中的 PI3K 或 Akt 蛋白（在体外和 PTLD 小鼠模型中），以利用我们的研究生化研究表明 PI3K/Akt/mTOR 失调是 EBV+ B 细胞的共同特征淋巴瘤。在目标 2 中，我们将确定负调节蛋白的缺陷是否在 EBV+ B 细胞淋巴瘤中 PI3K/Akt/mTOR 通路的组成型信号传导。我们还将评估如何 LMP1 基因的多样性影响通路激活并评估 LMP1 是否与宿主细胞合作 microRNA 网络破坏受感染 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 细胞同种异体激活和移植物存活的影响。我们还利用 LMP1 转基因小鼠模型，用于研究如何调节 PI3K/Akt/mTOR 中的特定节点途径改变移植受者中 B 细胞淋巴瘤的生长。这些研究将创造新的机会改善EBV+ PTLD的治疗，也将增加我们对EBV+ B细胞的基本了解淋巴瘤生物学和对同种异体移植物的免疫反应。