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

基本信息

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
项目类别：
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

项目摘要

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.

发现治疗多发性骨髓瘤 (MM) 的新治疗靶点并阐明它们的潜在分子机制对于治疗这种疾病的进展是必要的疾病。尽管最近在治疗多发性骨髓瘤方面取得了重大进展，例如使用蛋白酶体抑制剂的反应率 > 70%，疾病不可避免地会复发并持续存在无法治愈的。癌基因 c-Myc 是 MM 的关键驱动因素；超过60%的MM被激活近80%的蛋白酶体抑制剂难治性MM。然而，直接抑制c-的药物 Myc 还不存在，主要是因为 c-Myc 是一种转录因子，并且缺乏定义的三- 小分子可以结合的空间结构和口袋。除了 c-Myc 之外， MM 细胞的生存强烈依赖于泛素-蛋白酶体系统，因为由蛋白酶体抑制剂证明。在这个提案中，我们将测试以下假设：通过小泛素样修饰剂（SUMO）靶向翻译后修饰可以抑制 c-Myc 依赖性途径，还提供克服蛋白酶体抑制剂的方法反抗。拟议的研究基于我们的初步发现，即 SUMO 修饰调节 MM 细胞中的 c-Myc 蛋白水平和活性。此外，我们初步研究结果表明，硼替佐米（蛋白酶体抑制剂）耐药机制不仅可以依赖SUMO修饰，也可以使蛋白酶体功能更多耐药 MM 细胞比敏感 MM 细胞依赖 SUMO 修饰。我们建议阐明 SUMOylation 如何参与调节 c-Myc 水平的机制功能。此外，我们将阐明 SUMOylation 在人们知之甚少的领域中的作用蛋白酶体抑制剂耐药性的机制。我们还将验证初始体外动物模型中的发现。这些研究将通过我们拥有的 SUMO E1 抑制剂来实现过去几年一直在发展。拟议的研究可能会建立一种新颖的通过靶向治疗和治疗 MM 的治疗靶点和机制通过提供治疗方法来克服对蛋白酶体抑制的抵抗力。抑制 SUMO 化还可以解决大量其他具有耐药性的癌症通过开发对 c-Myc 驱动的癌症有效的药物来替代传统疗法。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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.