Targeting Mdm2-MdmX E3 Ligase for Treatment of Drug-Resistant Lymphoma

靶向 Mdm2-MdmX E3 连接酶治疗耐药淋巴瘤

• 批准号: 9898330
• 负责人: Xinjiang Wang
• 金额: $ 39.3万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898330
• 关键词: Address; Adult; Apoptosis; Apoptotic; B-Cell Lymphomas; Binding; Biochemistry; Cell Death Induction; Cell Line; Cells; Cessation of life; Clinic; Complex; Coupled; Cultured Cells; Cyclophosphamide; Data; Development; Doxorubicin; Drug Targeting; Drug resistance; Genetic; Goals; Hematologic Neoplasms; Hybrids; Inferior; Lead; Lymphoma; Lymphoma cell; Lymphomagenesis; Methods; Modeling; Mus; Mutate; Mutation; Non-Hodgkin' s Lymphoma; Null Lymphocytes; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Play; Polyubiquitination; Prednisone; Property; Protein Array; Public Health; Reaction; Recurrence; Refractory; Regulation; Relapse; Research; Resistance; Resistance development; Resolution; Role; SCID Mice; Solid; Stress; TP53 gene; Testing; Therapeutic; Transgenic Mice; Transgenic Model; Transplantation; Treatment Efficacy; Tube; Ubiquitination; Vincristine; X-Ray Crystallography; Xenograft procedure; acquired drug resistance; antitumor effect; base; biophysical analysis; chemotherapy; clinical translation; collaborative trial; cytotoxicity; design; genome-wide; high throughput screening; improved; improved outcome; in vivo; inhibitor/antagonist; innovation; large cell Diffuse non-Hodgkin' s lymphoma; lead optimization; leukemia/lymphoma; mouse model; new therapeutic target; novel therapeutics; outcome forecast; overexpression; patient response; prospective; relapse patients; resistance mechanism; response; rituximab; small molecule inhibitor; targeted treatment; therapy resistant; three dimensional structure; ubiquitin-protein ligase

B-cell lymphoma accounts for 88% Non-Hodgkin's lymphoma (NHL) which is the most common hematological malignancy in adults. The standard therapy for B-cell lymphoma is the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (i.e. R-CHOP). However, 60% of responsive patients develop resistance to rituximab and chemotherapy. Acquired drug resistance, therefore, is one of the major obstacles to successfully treating patients with NHL. Results of the prospective multicenter phase III Collaborative trial in relapsed aggressive lymphoma (CORAL) stressed the need to for novel therapeutic strategies to treat relapsed/refractory lymphoma. The p53 pathway plays a pivotal role in drug response: wild type p53 patients respond to R-CHOP well while p53-mutated patients respond poorly. Among the p53- mutated patients, Mdm2 overexpression predicts inferior prognosis. Therefore, targeting Mdm2 E3 ligase and induction of cell death in p53-mutated patients are attractive therapeutic strategies for improved outcome in relapsed/refractory patients. In this regards, Inhibitors targeting the E3 ligase activity of Mdm2-MdmX E3 complex would elicit p53-dependent and p53-independent apoptosis in lymphomas because (1) Mdm2-MdmX E3 complex plays an essential role in negative regulation of p53 and their inhibition will activate p53 and (2) Mdm2-MdmX are involved in p53-independent anti-death mechanisms. Therefore, our central hypothesis is that targeting Mdm2-MdmX E3 ligase activity is a new strategy to treat relapsed/refractory lymphoma via p53- dependent and p53-independent mechanisms. The inhibitors for Mdm2-MdmX E3 ligase will provide new options for lymphoma patients who are resistant to R-CHOP therapy in clinics. However, there are no inhibitors available for Mdm2-MdmX E3 complex. In a high throughput screening effort, we successfully identified small molecule inhibitors that specifically inhibit Mdm2-MdmX E3 activity (designated as MMRi) and they induce p53-dependent and p53-indpendent apoptosis in drug-resistant lymphoma cells. The objective of this application is to examine the therapeutic efficacy of MMRi36 in xenograft lymphoma models of rituximab- resistant lymphoma and in transgenic models of MdmX-driven lymphoma in Aim1 and elucidate the mechanisms of action of MMRi in Aim2 and resolve the 3-D structures of Mdm2-MdmX-MMRi complex in Aim3 for lead optimization and clinical translation of MMRi. The long term goal of this research is to develop targeted therapies and their combinations for better treatment of drug-resistant lymphoma. The proposed research is highly innovative because our MMRis are first-in-class inhibitors with potent anti-lymphoma activity, particularly against drug-resistant lymphoma cells. The proposed research is significant because it addresses a critical gap in lymphoma management and may lead to development of a novel targeted therapy for recurrent lymphoma and provide a new option for ~60% relapsed lymphoma patients after R-CHOP.

B细胞淋巴瘤占88％的非霍奇金淋巴瘤（NHL），这是最常见的 成人血液系统恶性肿瘤。 B细胞淋巴瘤的标准疗法是利妥昔单抗的结合， 环磷酰胺，阿霉素，长春新碱和泼尼松（即R-Chop）。但是，有60％的响应能力 患者对利妥昔单抗和化学疗法产生抗药性。因此，获得的耐药性是 成功治疗NHL患者的主要障碍。前瞻性多中心III的结果 复发性侵袭性淋巴瘤（珊瑚）的协作试验强调了新型治疗的必要性 治疗复发/难治性淋巴瘤的策略。 p53途径在药物反应中起关键作用：野生 p53型患者对R-CHOP的反应良好，而P53突变患者反应不佳。在p53-中 突变的患者MDM2的过表达预测了下的预后。因此，针对MDM2 E3连接酶和 p53突变患者的细胞死亡诱导是有吸引力的治疗策略，可改善预后 复发/难治性患者。在这个方面，针对MDM2-MDMX E3的E3连接酶活性的抑制剂 复合物会引起淋巴瘤中p53依赖性和p53独立凋亡，因为（1）MDM2-MDMX E3复合物在p53负调节中起着至关重要的作用，其抑制作用将激活p53和（2） MDM2-MDMX参与了p53独立的抗死亡机制。因此，我们的中心假设是 靶向MDM2-MDMX E3连接酶活性是一种通过p53-处理复发/难治性淋巴瘤的新策略。 依赖和p53无关的机制。 MDM2-MDMX E3连接酶的抑制剂将提供新的 抗诊所R-CHOP治疗的淋巴瘤患者的选择。但是，没有 可用于MDM2-MDMX E3复合物的抑制剂。在高吞吐量筛查中，我们成功地 鉴定出特异性抑制MDM2-MDMX E3活性（指定为MMRI）的小分子抑制剂和 它们诱导抗药性淋巴瘤细胞中的p53依赖性和p53诱导凋亡。目的 该应用是为了检查MMRI36在利妥昔单抗的异种移植淋巴瘤模型中的治疗功效 在AIM1中，抗性淋巴瘤和MDMX驱动的淋巴瘤的转基因模型，并阐明 MMRI在AIM2中的作用机制并解决MDM2-MDMX-MMRI复合物中的3-D结构 AIM3用于MMRI的铅优化和临床翻译。这项研究的长期目标是发展 靶向疗法及其组合，以更好地治疗药物耐药性淋巴瘤。提议 研究具有很高的创新性，因为我们的MMRI是具有有效抗淋巴瘤的第一类抑制剂 活性，特别是针对耐药性淋巴瘤细胞的活性。拟议的研究很重要，因为它 解决淋巴瘤管理中的危险差距，并可能导致新的靶向疗法的发展 对于复发性淋巴瘤，R-CHOP后约60％复发淋巴瘤患者提供了新的选择。