Non-genotoxic p53 activation as novel therapeutic concept for lymphoma

非基因毒性 p53 激活作为淋巴瘤的新治疗概念

基本信息

批准号：
7715218
负责人：
MICHAEL ANDREEFF
金额：
$ 6.8万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7715218
关键词：
Acute Acute Myelocytic Leukemia Acute leukemia Aftercare Apoptosis Apoptotic BCL2 gene Binding Blast Cell Blood Cancer Center Cell Cycle Cell Death Cell Line Cells Cellular Stress Chronic Lymphocytic Leukemia Clinical Clinical Data Clinical Trials Coculture Techniques Combination Drug Therapy Complex Custom Cytarabine DNA Damage Data Daunorubicin Development Doctor of Medicine Dose Dose-Limiting Double Minutes Drug Kinetics Effectiveness Employee Strikes Family member Future Genes Genetic Genetic Transcription Goals Hematologic Neoplasms Hodgkin Disease Homologous Gene Human Incidence Induction of Apoptosis Instruction Lead Lymphoid Lymphoma MAP Kinase Gene MCL1 protein MDM2 gene MDM2 gene Marrow Maximum Tolerated Dose Mediating Mitochondria Mitogen-Activated Protein Kinase Inhibitor Molecular Mus Mutagens Mutate Mutation Myelogenous Newly Diagnosed Non-Hodgkin&apos s Lymphoma Oral PMAIP1 gene Patients Phase Phase I Clinical Trials Protein p53 Proteins Relapse Reporting Reproduction spores Resistance Signal Transduction Small Interfering RNA Solid Neoplasm Stem cells Suspension Culture System TP53 gene Testing Therapeutic Toxic effect Treatment outcome Tumor Suppressor Proteins Ubiquitin-mediated Proteolysis Pathway analog base chemotherapeutic agent chemotherapy clinical effect design fludarabine improved in vivo inhibitor/antagonist leukemia man mimetics mutant novel novel therapeutics overexpression pre-clinical protein protein interaction response restoration small hairpin RNA small molecule synergism trafficking ubiquitin ligase

项目摘要

The primary goal of this project is to improve treatment outcome and the cure rate of lymphoma, by introducing novel therapeutic strategies. The main therapeutic challenge in the treatment of lymphomas is the development of strategies that maximize the induction of lymphoma cell apoptosis before resistance to chemotherapy develops. p53 and Bcl-2 are the master switches that determine whether a stressed cell undergoes apoptosis, thus acting as tumor suppressors. We have recently reported that restoration of p53 activity by inhibiting the HDM2/p53 interaction utilizing non-genotoxic small molecule inhibitors (Nutlin 3a, Ml 63) induces apoptosis in CLL, lymphomas (Hodgkin's and Non-Hodgkin's), and in lymphoid and myeloid acute leukemias with unmutated p53. While these HDM2 inhibitors dramatically increase p53 levels which in turn initiate transcription of p53 targets, transcription-independent direct interactions of p53 with Bcl-2 family members do also occur. We reported striking synergisms of HDM2 inhibitors with conventional chemotherapeutic agents such as fludarabine, cytarabine and daunorubicin, and with MAPK inhibitors, which we found to regulate the subcellular distribution of p53 and to inhibit induction of anti-apoptotic p21. Bcl-2 and some of its anti-apoptotic family members are overexpressed in lymphomas, including CLL, and are potential inhibitors of p53 activation-induced mitochondrial apoptotic signaling. We and others have reported that functional inhibition of Bcl-2 by BH3-mimetics (e.g. ABT-737) induces mitochondrial apoptosis and synergizes with chemotherapy. However, we reported that ABT-737 does not bind to Mcl-1. In leukemias, Mcl-1 can be completely downregulated by MAPK (pERK) inhibition, resulting in unprecedented synergism with ABT-737 in inducing apoptosis. In Aim 1 we propose to identify the molecular determinants of apoptosis induced by non-genotoxic small molecule inhibitors of HDM2 (Nufiin 3a, Ml 63) in CLL and lymphoma cell lines and primary CLL/SLL cells. In Aim 2 we will determine mechanisms by which HDM2 inhibifion synergizes with BH3 mimefics, MAPK inhibitors and chemotherapy, and in Aim 3 we will conduct the first-in-man Phase 1 trial of a HDM2 inhibitor (Nufiin 3a analog R05045337) in CLL/SLL. These studies will provide rationale for the development of novel therapeufic strategies in lymphomas based on the non- genotoxic disruption of protein-protein interactions resulfing in activation of p53 signaling and inhibition of Bcl-2 function. RELEVANCE (See Instructions): CLL Is a largely incurablo leukemia with increasing incidence and novel therapeutic concepts are urgently needed. In this proposal, we will take advantage of the recent discovery that p53 is rarely mutated in CLL, but frequently inactivated by over-expressed HDM2. We have demonstrated that disrupfion of the MDM2 / p53 complex by Nufiin results in the non-genotoxic activafion of p53 signaling and apoptosis in CLL . Beyond mechanisfic studies of p53 acfivafion and inhibition of the second major anfi-apoptotic gene (Bcl-2), we will conduct the first human trial of Nutlin in man, with the goal of evaluafing this novel therapeufic concept in CLL.

该项目的主要目标是通过以下方式改善淋巴瘤的治疗结果和治愈率：引入新的治疗策略。淋巴瘤治疗的主要挑战是制定在耐药之前最大限度地诱导淋巴瘤细胞凋亡的策略化疗发生。 p53和Bcl-2是决定应激细胞是否处于应激状态的主开关经历细胞凋亡，从而起到肿瘤抑制因子的作用。我们最近报道了 p53 的恢复利用非基因毒性小分子抑制剂（Nutlin 3a，Ml）抑制 HDM2/p53 相互作用来发挥活性 63) 诱导 CLL、淋巴瘤（霍奇金病和非霍奇金病）以及淋巴和骨髓细胞凋亡 p53 未突变的急性白血病。虽然这些 HDM2 抑制剂显着增加了 p53 水平，转启动 p53 靶标的转录，p53 与 Bcl-2 家族的转录独立的直接相互作用成员也确实发生。我们报告了 HDM2 抑制剂与传统药物具有显着的协同作用化疗药物，如氟达拉滨、阿糖胞苷和柔红霉素，以及 MAPK 抑制剂，我们发现它可以调节 p53 的亚细胞分布并抑制抗凋亡 p21 的诱导。 Bcl-2 它的一些抗凋亡家族成员在淋巴瘤（包括 CLL）中过度表达，并且 p53 激活诱导的线粒体凋亡信号传导的潜在抑制剂。我们和其他人已经报道过 BH3 模拟物（例如 ABT-737）对 Bcl-2 的功能性抑制会诱导线粒体凋亡，与化疗有协同作用。然而，我们报道 ABT-737 不与 Mcl-1 结合。在白血病中， Mcl-1 可通过 MAPK (pERK) 抑制完全下调，从而产生前所未有的协同作用与 ABT-737 一起诱导细胞凋亡。在目标 1 中，我们建议确定以下因素的分子决定因素： CLL 和 HDM2 的非基因毒性小分子抑制剂（Nufiin 3a、Ml 63）诱导细胞凋亡淋巴瘤细胞系和原代 CLL/SLL 细胞。在目标 2 中，我们将确定 HDM2 的机制抑制与 BH3 模拟物、MAPK 抑制剂和化疗具有协同作用，在目标 3 中我们将进行 HDM2 抑制剂（Nufiin 3a 类似物 R05045337）治疗 CLL/SLL 的首次人体 1 期试验。这些研究将为基于非非治疗方法的淋巴瘤新治疗策略的开发提供理论依据蛋白质-蛋白质相互作用的基因毒性破坏导致 p53 信号传导的激活和抑制 Bcl-2 功能。相关性（参见说明）：CLL 是一种发病率不断增加且新型的白血病，很大程度上是一种不可治愈的白血病。迫切需要治疗概念。在这个提案中，我们将利用最近的发现 p53 在 CLL 中很少发生突变，但经常被过度表达的 HDM2 失活。我们有证明 Nufiin 破坏 MDM2 / p53 复合物会导致非基因毒性激活 CLL 中的 p53 信号传导和细胞凋亡。除了 p53 激活和抑制的机制研究之外第二个主要抗凋亡基因（Bcl-2），我们将在人体中进行 Nutlin 的首次人体试验，目标评估 CLL 中这一新颖的治疗概念。