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：
7975984
负责人：
ROBERT ZYGMUNT ORLOWSKI
金额：
$ 17.89万
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：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7975984
关键词：
Agonist Anthracyclines Apoptosis Apoptotic Autophagocytosis Biological Models Biology Bortezomib 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 TP53 gene Testing Toxic effect Translating Transplantation Treatment Efficacy Tumor Suppressor Proteins Type I Epithelial Receptor Cell Type II Epithelial Receptor Cell Ubiquitin Velcade 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-蛋白酶体途径已被验证为多发性骨髓瘤 (MM) 的治疗靶点我们小组和其他人通过证明硼替佐米在复发/难治性癌症中的活性和 up-ft-ont 设置。然而，由于其对细胞内蛋白水解作用的广泛影响，这种蛋白酶体抑制剂在分子水平上诱导抗凋亡作用，从而降低其功效，并且在临床上它会引起周围神经病变等毒性，从而限制了其实用性。更有针对性的方法，因此，例如通过抑制特定的 E3 泛素连接酶，该酶仅负责一小部分的泛素化客户蛋白的子集可能会更有效且耐受性更好。我们已经获得证据表明 HDM-2 E3 连接酶的第二代小分子抑制剂，该酶以其在 p53 中的作用而闻名泛素化，在 MM 模型中诱导抗增殖作用，无论其 p53 状态如何；那些药物激活 p53 依赖性 I 型细胞死亡程序，以及 p53 独立的 II 型细胞死亡程序，或自噬；并且它们在野生型和不同类型的化疗药物中具有协同作用突变 p53 背景。这些和其他发现使我们得出了我们的中心假设，即 HDM-2 抑制剂是有前景的新型药物，可在 p53 状态适应方法中用作化学增敏剂个性化 MM 治疗。为了评估这种可能性，并将这些药物转化为临床，我们提出的具体目标将： 1. 进一步明确 HDM-2 抑制剂在 MM 中作用的分子机制，包括它们对 I 型和 II 型细胞死亡的影响，以及 p53 和 HDM-2 在这些过程中的作用； 2. 描述 HDM-2 抑制剂使 MM 对 L 型诱导化疗药物敏感的途径，例如在野生型 p53 模型中作为蒽环类药物、死亡受体激动剂和 Bcl-2 抑制剂，以及 mTOR 突变 p53 模型中的抑制剂； 3. 在 I 期研究中试用 HDM-2 抑制剂作为单一药物评估其对复发/难治性 MM 患者细胞死亡诱导的影响和机制为后续个体化 p53 状态适应方法的研究做好准备。