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

B细胞淋巴瘤占88%，非霍奇金淋巴瘤（NHL）是最常见的 成人血液恶性肿瘤。B细胞淋巴瘤的标准疗法是利妥昔单抗， 环磷酰胺、多柔比星、长春新碱和泼尼松（即R-CHOP）。60%的响应 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 成功治疗NHL患者的主要障碍。前瞻性多中心III期研究的结果 复发性侵袭性淋巴瘤（CORAL）的合作试验强调了对新治疗方法的需求 治疗复发性/难治性淋巴瘤的策略。p53通路在药物反应中起着关键作用：野生型 p53型患者对R-CHOP反应良好，而p53突变患者反应较差。在p53中- 突变的患者，Mdm 2过表达预测较差的预后。因此，靶向Mdm 2 E3连接酶和 在p53突变患者中诱导细胞死亡是改善 复发/难治性患者。在这方面，针对Mdm 2-MdmX E3的E3连接酶活性的抑制剂 Mdm 2-MdmX复合物可诱导淋巴瘤中p53依赖性和p53非依赖性细胞凋亡，因为（1）Mdm 2-MdmX复合物可诱导淋巴瘤中p53依赖性和p53非依赖性细胞凋亡， E3复合物在p53的负调节中起重要作用，它们的抑制将激活p53和（2） Mdm 2-MdmX参与p53非依赖性抗死亡机制。因此，我们的中心假设是 靶向Mdm 2-MdmX E3连接酶活性是一种通过p53- 依赖性和p53非依赖性机制。Mdm 2-MdmX E3连接酶的抑制剂将提供新的 临床上对R-CHOP治疗耐药的淋巴瘤患者的选择。但没有 Mdm 2-MdmX E3复合物的抑制剂。在高通量筛选工作中，我们成功地 鉴定了特异性抑制Mdm 2-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不依赖性细胞凋亡。的目标 本申请是为了检查MMRi 36在利妥昔单抗的异种移植淋巴瘤模型中的治疗功效。 耐药淋巴瘤和MdmX驱动的淋巴瘤转基因模型中的Aim 1，并阐明 MDMR 1在Aim 2中的作用机制，并解析Aim 2中Mdm 2-MdmX-MMR 1复合物的3-D结构。 Aim 3用于MMRI的电极导线优化和临床转化。这项研究的长期目标是开发 靶向治疗及其组合，以更好地治疗耐药淋巴瘤。拟议 研究是高度创新的，因为我们的MMRis是具有强效抗淋巴瘤的一流抑制剂 活性，特别是针对耐药性淋巴瘤细胞。这项研究意义重大，因为它 解决了淋巴瘤管理中的一个关键空白，并可能导致新的靶向治疗的发展 为约60%的复发淋巴瘤患者提供了新的选择。

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.