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

基本信息

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
项目类别：
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&apos 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&apos 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

项目摘要

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% 非霍奇金淋巴瘤 (NHL)，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联合使用利妥昔单抗、环磷酰胺、阿霉素、长春新碱和泼尼松（即 R-CHOP）。然而，60% 的受访者患者对利妥昔单抗和化疗产生耐药性。因此，获得性耐药性是其中之一成功治疗 NHL 患者的主要障碍。前瞻性多中心 III 期结果复发性侵袭性淋巴瘤（CORAL）的合作试验强调需要新的治疗方法治疗复发/难治性淋巴瘤的策略。 p53 通路在药物反应中发挥着关键作用：野生 p53 型患者对 R-CHOP 反应良好，而 p53 突变患者反应较差。其中p53- 在突变患者中，Mdm2 过度表达预示预后较差。因此，针对 Mdm2 E3 连接酶和 p53 突变患者的细胞死亡诱导是改善预后的有吸引力的治疗策略复发/难治性患者。在这方面，针对 Mdm2-MdmX E3 的 E3 连接酶活性的抑制剂复合物会在淋巴瘤中引发 p53 依赖性和 p53 依赖性细胞凋亡，因为 (1) Mdm2-MdmX E3 复合物在 p53 的负调节中发挥重要作用，其抑制将激活 p53 和 (2) Mdm2-MdmX 参与 p53 独立的抗死亡机制。因此，我们的中心假设是靶向 Mdm2-MdmX E3 连接酶活性是通过 p53- 治疗复发/难治性淋巴瘤的新策略依赖和 p53 独立机制。 Mdm2-MdmX E3 连接酶抑制剂将提供新的为临床上对 R-CHOP 疗法耐药的淋巴瘤患者提供选择。然而，没有可用于 Mdm2-MdmX E3 复合物的抑制剂。在高通量筛选工作中，我们成功鉴定出特异性抑制 Mdm2-MdmX E3 活性的小分子抑制剂（命名为 MMRi）它们在耐药淋巴瘤细胞中诱导 p53 依赖性和 p53 依赖性细胞凋亡。的目标本申请旨在检验 MMRi36 在利妥昔单抗异种移植淋巴瘤模型中的治疗效果耐药性淋巴瘤和 Aim1 中 MdmX 驱动的淋巴瘤转基因模型，并阐明 MMRi 在 Aim2 中的作用机制并解析 Mdm2-MdmX-MMRi 复合物的 3-D 结构 Aim3 用于 MMRi 的先导化合物优化和临床转化。这项研究的长期目标是开发靶向治疗及其组合可以更好地治疗耐药淋巴瘤。拟议的研究具有高度创新性，因为我们的 MMRis 是具有强效抗淋巴瘤作用的一流抑制剂活性，特别是针对耐药淋巴瘤细胞。拟议的研究意义重大，因为它解决了淋巴瘤治疗中的一个关键差距，并可能导致新型靶向疗法的开发治疗复发性淋巴瘤，为 R-CHOP 后约 60% 的复发性淋巴瘤患者提供新的选择。