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

• 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
• 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

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， 我们的小组和其他人通过证明硼替佐米在复发性/难治性 和向上的设置。然而，由于其对细胞内蛋白水解的广泛影响， 抑制剂在分子水平上诱导抗凋亡作用，降低其疗效，在临床上， 水平上，它会引起周围神经病变等毒性，从而限制了它的使用。更有针对性的方法， 因此，例如通过抑制一种特定的E3泛素连接酶， 客户蛋白的子集，可能更有效和更好的耐受性。我们有证据表明 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，而不管它们的p53状态如何;这些 药剂激活p53依赖性I型细胞死亡程序以及p53非依赖性II型细胞死亡，或 自噬作用;并且它们与野生型中不同类别的化疗剂协同相互作用， 突变型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 是有前途的新型药物，可用作p53状态适应性方法中的化学增敏剂， 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，我们的 拟议的具体目标将：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. 阐明HDM-2抑制剂使MM对l型诱导化疗药物敏感的途径， 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， 突变型p53模型中的抑制剂;和3.在I期研究中将HDM-2抑制剂作为单药进行试验 评估其在复发性/难治性MM患者中诱导细胞死亡的影响和机制， 为以后研究个体化p53状态适应性方法奠定基础。