P3 - TARGETING THE HDM-2 E3 LIGASE IN MULTIPLE MYELOMA

P3 - 靶向多发性骨髓瘤中的 HDM-2 E3 连接酶

基本信息

批准号：
8326170
负责人：
ROBERT ZYGMUNT ORLOWSKI
金额：
$ 17.12万
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/8326170
关键词：
Agonist Anthracyclines Apoptosis Apoptotic Autophagocytosis Biological Models Biology Bortezomib Cancer Center Cell Death Cell Death Induction Cell Line Cells Cessation of life Characteristics Chemosensitization Client Clinic Clinical Clinical Trials Cyclin-Dependent Kinase Inhibitor DNA Damage Data Dependence Diagnosis Disease Dose Dose-Limiting Double Minutes Family member Gene Expression Generations Heat Shock Protein 27 Heat shock proteins Hematologic Neoplasms Homologous Gene Human Ligase Lymphoma Maximum Tolerated Dose Mediating Melphalan Mitogen-Activated Protein Kinases Modeling Molecular Multiple Myeloma Mus NF-kappa B Outcome Pathway interactions Patients Peripheral Nervous System Diseases Pharmaceutical Preparations Phase I Clinical Trials Phosphoric Monoester Hydrolases Plasma Cells Prednisone Process Proteasome Inhibitor Protein Family Proteins Proteolysis Proto-Oncogene Proteins c-akt Refractory Regimen Relapse Reporting Role Sirolimus Sterically Stabilized Liposome Testing Toxic effect Translating Transplantation Treatment Efficacy Tumor Suppressor Proteins Type I Epithelial Receptor Cell Type II Epithelial Receptor Cell Ubiquitin chemosensitizing agent clinical efficacy clinically relevant design drug candidate functional status in vitro activity in vivo in vivo Model inhibitor/antagonist mTOR protein member multicatalytic endopeptidase complex mutant novel partial response phase 1 study pre-clinical programs receptor small molecule therapeutic target tumor ubiquitin-protein ligase

项目摘要

The ubiquitin-proteasome pathway has been validated as a therapeutic target for mulfiple myeloma (MM) by our group and others through the demonstrafion ofthe acfivity of bortezomib in both the relapsed/refractory and up-ft-ont settings. Because of its broad impact on intracellular proteolysis, however, this proteasome inhibitor induces anfi-apoptotic effects at the molecular level that decrease its efficacy, and at the clinical level it induces toxicifies such as peripheral neuropathy that limit its ufility. A more targeted approach, therefore, such as by inhibiting a specific E3 ubiquitin ligase responsible for ubiquitinafion of only a small subset of client proteins, would likely be more effective and better tolerated. We have obtained evidence that second-generation small molecule inhibitors ofthe HDM-2 E3 ligase, which is best known for its role in p53 ubiquitinafion, induce anfi-proliferative effects in MM models irrespective of their p53 status; that these agents activate a p53-dependent type I cell death program, as well as p53-independent type II cell death, or autophagy; and that they interact synergistically with different classes of chemotherapeutics in wild type and mutant p53 backgrounds. These and other findings led us to our central hypothesis, that HDM-2 inhibitors are promising novel agents that can be used as chemosensitizers in a p53 status-adapted approach to personalize MM therapy. To evaluate this possibility, and to translate these agents into the clinic, our proposed specific aims will: 1. Further define the molecular mechanisms of acfion of HDM-2 inhibitors in MM, including their impact on type I and II cell death, and the role of p53 and HDM-2 in these processes; 2. Delineate the pathways by which HDM-2 inhibitors sensifize MM to type l-inducing chemotherapeutics such as anthracyclines, death receptor agonists, and Bcl-2 inhibitors in wild type p53 models, and to mTOR inhibitors in mutant p53 models; and 3. Pilot an HDM-2 inhibitor as a single agent in a phase I study evaluafing its impact and mechanism of cell death induction in patients with relapsed/refractory MM in preparafion for later studies of an individualized p53 status-adapted approach.

泛素 - 蛋白酶体途径已被证实是Mulfiple骨髓瘤（MM）的治疗靶点我们的小组和其他人在复发/难治性中的硼替佐米的抗性证明和上限设置。然而，由于其对细胞内蛋白水解的影响广泛，因此该蛋白酶体抑制剂在分子水平上诱导ANFI凋亡作用，从而降低其疗效它诱导毒性的水平，例如限制其不可利益度的周围神经病。一种更具针对性的方法，因此，例如，通过抑制特定的E3泛素连接酶客户蛋白的子集可能会更有效，更耐受。我们有证据表明 HDM-2 E3连接酶的第二代小分子抑制剂，该抑制剂以其在p53中的作用而闻名泛素化，无论其p53状态如何，都会在MM模型中诱导Anfi增殖效应；这些代理激活依赖p53的I型细胞死亡程序，以及独立于p53的II型细胞死亡或自噬；并且它们与野生类型的不同类别的化学治疗剂协同相互作用，突变p53背景。这些和其他发现导致我们提出了中心假设，即HDM-2抑制剂是有前途的新型药物，可以用作p53状态的方法中的化学效应器个性化MM疗法。为了评估这种可能性，并将这些药物转化为诊所提出的特定目的将：1。进一步定义了MM中HDM-2抑制剂的分子机制，包括它们对I型和II细胞死亡的影响，以及p53和HDM-2在这些过程中的作用； 2。描绘HDM-2抑制剂敏感MM诱导L-2诱导化学治疗剂的途径作为蒽环类药物，野生型p53模型中的死亡受体激动剂和Bcl-2抑制剂突变体p53模型中的抑制剂；和3。在I期研究中，HDM-2抑制剂作为单个药物评估其复发/难治性MM患者细胞死亡诱导的影响和机制准备以后研究个性化p53状态适应的方法。