Targeting c-Myc and Proteasome Inhibitor Resistance in Multiple Myeloma

靶向多发性骨髓瘤中的 c-Myc 和蛋白酶体抑制剂耐药性

• 批准号: 9942394
• 负责人: Yuan Chen
• 金额: $ 53.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9942394
• 关键词: Address; Affect; Animal Model; Antineoplastic Agents; Automobile Driving; Binding; Bone Marrow; Bortezomib; Catalytic Domain; Cell Line; Cells; Clinical Research; Data; Data Set; Disease; Disease model; Enzymes; FDA approved; Genetic; Hematologic Neoplasms; Human; Hyperactivity; In Vitro; Lead; MYC gene; Malignant Neoplasms; Modification; Molecular; Multiple Myeloma; Mus; Oncogenes; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Post-Translational Protein Processing; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Proto-Oncogene Proteins c-myc; Publishing; Refractory; Relapse; Resistance; Resistance development; Role; Safety; Sampling; Sumoylation Pathway; System; Testing; Therapeutic; Translations; Ubiquitin; United States; Xenograft procedure; anticancer research; base; c-myc Genes; cancer type; chemotherapy; conventional therapy; cytotoxic; improved; inhibitor/antagonist; innovation; interest; knock-down; mouse model; multicatalytic endopeptidase complex; new therapeutic target; novel; novel strategies; overexpression; pre-clinical; predictive marker; proteostasis; refractory cancer; relapse patients; resistance mechanism; response; small molecule; targeted treatment; therapeutic target; therapy development; therapy resistant; three dimensional structure; transcription factor; tumor growth; tumorigenesis

The discovery of new therapeutic targets for treating multiple myeloma (MM) and elucidating their underlying molecular mechanisms are necessary for the progress in treatment of this disease. Despite significant recent progress in treating MM, such as the use of proteasome inhibitors, which have a > 70% response rate, the disease inevitably relapses and remains incurable. The oncogene c-Myc is a key driver in MM; it is activated in more than 60% of MM and in nearly 80% of proteasome inhibitor refractory MM. However, drugs that directly inhibit c- Myc do not yet exist, largely because c-Myc is a transcription factor and lacks a defined three- dimensional structure and pockets to which small molecules can bind. In addition to c-Myc, MM cells are strongly dependent on the ubiquitin-proteasome system for survival, as demonstrated by the proteasome inhibitors. In this proposal, we will test the hypothesis that targeting post-translational modifications by the small ubiquitin-like modifier (SUMO) can inhibit c-Myc-dependent pathways and also provide a means for overcoming proteasome inhibitor resistance. The proposed studies are based on our preliminary findings that SUMO modification regulates c-Myc protein levels and activity in MM cells. In addition, our preliminary findings suggest that the mechanisms of bortezomib (proteasome inhibitor) resistance not only could depend on SUMO modification, but also could render proteasome function more dependent on SUMO modification in resistant than in sensitive MM cells. We propose to elucidate the mechanism of how SUMOylation is involved in regulating c-Myc levels and function. In addition, we will elucidate the role of SUMOylation in the poorly understood mechanisms underlying proteasome inhibitor resistance. We will also validate initial in vitro findings in animal models. These studies will be enabled by SUMO E1 inhibitors that we have been developing over the last few years. The proposed studies will likely establish a novel therapeutic target and mechanism for the treatment of MM by offering targeted therapies and by providing therapeutic approaches to overcome resistance to proteasome inhibition. Inhibition of SUMOylation could also address a large population of other cancers that resist conventional therapies by developing drugs that are efficacious against c-Myc-driven cancers.

发现用于治疗多发性骨髓瘤（MM）并阐明的新治疗靶标 它们的基本分子机制对于治疗的进展是必要的 疾病。尽管最近在治疗MM方面取得了重大进展，例如使用蛋白酶体 抑制剂的缓解率> 70％，该疾病不可避免地复发，并且仍然存在 无法治愈。癌基因C-MYC是MM中的关键驱动器；它在超过60％的MM中被激活 并在近80％的蛋白酶体抑制剂难治性MM中。但是，直接抑制c-的药物 MYC还不存在，主要是因为C-MYC是转录因子，并且缺乏定义的三个 - 小分子可以结合的尺寸结构和口袋。除了C-Myc， MM细胞强烈依赖于生存的泛素 - 蛋白酶体系统，如 由蛋白酶体抑制剂证明。在此提案中，我们将检验以下假设 针对小型泛素样修饰剂（SUMO）靶向翻译后修饰可以抑制 C-MYC依赖性途径，还为克服蛋白酶体抑制剂提供了一种手段 反抗。拟议的研究基于我们的初步发现 修饰调节C-MYC蛋白水平和MM细胞的活性。此外，我们的初步 调查结果表明，硼替佐米（蛋白酶体抑制剂）耐药的机制不仅 可能取决于相扑的修改，但也可能使蛋白酶体功能更大 取决于耐药性的SUMO修饰，而不是敏感的MM细胞中。我们建议 阐明Sumoylation如何参与调节C-MYC水平的机制和 功能。此外，我们将阐明sumoylation在不理会的知识中的作用 蛋白酶体抑制剂抗性的机制。我们还将验证初始体外 动物模型中的发现。这些研究将由Sumo E1抑制剂启用 在过去的几年中一直在发展。拟议的研究可能会建立小说 通过提供靶向疗法和 通过提供治疗方法来克服对蛋白酶体抑制的抵抗力。 抑制sumoylation也可以解决抗拒的其他大量癌症 传统的疗法通过开发有效的针对C-MYC驱动的癌症的药物。

项目成果

SUMOylation inhibition enhances dexamethasone sensitivity in multiple myeloma.

• DOI: 10.1186/s13046-021-02226-9
• 发表时间: 2022-01-04
• 期刊: Journal of experimental & clinical cancer research : CR
• 作者: Du L;Liu W;Aldana-Masangkay G;Pozhitkov A;Pichiorri F;Chen Y;Rosen ST
• 通讯作者: Rosen ST

Critical Non-Covalent Binding Intermediate for an Allosteric Covalent Inhibitor of SUMO E1.

• DOI: 10.1021/acs.jpclett.3c00253
• 发表时间: 2023-03-23
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY LETTERS
• 影响因子: 5.7
• 作者: Pawnikar, Shristi;Bhattarai, Apurba;Ouyang, S. Xiaohu;Vega, Ramir;Chen, Yuan;Miao, Yinglong
• 通讯作者: Miao, Yinglong

MEK162 Enhances Antitumor Activity of 5-Fluorouracil and Trifluridine in KRAS-mutated Human Colorectal Cancer Cell Lines.

• DOI: 10.21873/anticanres.11634
• 发表时间: 2017-06
• 期刊: Anticancer research
• 影响因子: 2
• 作者: Gong J;Chen Y;Yang L;Pillai R;Shirasawa S;Fakih M
• 通讯作者: Fakih M