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：
8120289
负责人：
MICHAEL ANDREEFF
金额：
$ 6.81万
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：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8120289
关键词：
Acute Acute Myelocytic Leukemia Acute leukemia Aftercare Apoptosis Apoptotic BCL2 gene Binding Blast Cell Blood 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 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 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.

该项目的主要目的是通过引入新颖的治疗策略。淋巴瘤治疗的主要治疗挑战是在抗性之前，发展淋巴瘤细胞凋亡的策略的发展化学疗法发展。 p53和bcl-2是确定压力细胞的主开关经历凋亡，因此充当肿瘤抑制因子。我们最近报道了p53的恢复通过使用非生物毒性的小分子抑制剂抑制HDM2/p53相互作用（Nutlin 3A，ML，ML）来活性 63）诱导CLL，淋巴瘤（Hodgkin和非霍奇金）以及淋巴机和髓样的凋亡急性白血病，未经未来的p53。这些HDM2抑制剂大大提高了p53水平转弯启动p53目标的转录，p53与Bcl-2家族的转录无关直接相互作用成员也确实发生了。我们报道了HDM2抑制剂的引人注目的协同作用化学治疗剂，例如氟达拉滨，细胞丁滨和杜申umubicin，以及MAPK抑制剂，这些抑制剂我们发现调节p53的亚细胞分布并抑制抗凋亡p21的诱导。 Bcl-2 其中一些抗凋亡家庭成员在包括CLL在内的淋巴瘤中过表达，并且是 p53激活诱导的线粒体凋亡信号的潜在抑制剂。我们和其他人报告了 BH3-Mimetics（例如ABT-737）对Bcl-2的功能抑制会诱导线粒体凋亡和与化学疗法协同作用。但是，我们报告说ABT-737与MCL-1不结合。在白血病中， MAPK（PERK）抑制可以完全下调MCL-1，导致前所未有的协同作用与ABT-737诱导凋亡。在AIM 1中，我们建议确定的分子决定因素由非生物毒性的小分子抑制剂（Nufiin 3a，ML 63）在CLL和CLL中诱导的凋亡淋巴瘤细胞系和原发性CLL/SLL细胞。在AIM 2中，我们将确定HDM2的机制抑制剂与BH3 MIMEFICS，MAPK抑制剂和化学疗法协同作用，在AIM 3中，我们将进行 HDM2抑制剂（NUFIIN 3A模拟R05045337）的第一阶段1期试验。这些研究将为基于非 - 蛋白质 - 蛋白质相互作用的遗传毒性破坏在激活p53信号传导中的激活和抑制 Bcl-2功能。相关性（请参阅说明）：CLL是一种在很大程度上是Incurablo白血病，发病率和新颖迫切需要治疗概念。在此提案中，我们将利用最近的发现该p53在CLL中很少突变，但经常被过表达的HDM2灭活。我们有证明了Nufiin对MDM2 / p53复合物的解散导致非生物毒性活化酶 CLL中的p53信号传导和凋亡。除了对p53 acfivafion的机械性研究和抑制第二个主要的Anfi凋亡基因（BCL-2），我们将在人类中进行Nutlin的第一个人类试验，其目标在CLL中评估这种新颖的治疗概念。