Dissecting and targeting canonical and non-canonical oncogenic functions of EZH2 in caner

剖析和靶向 EZH2 在癌症中的典型和非典型致癌功能

基本信息

批准号：
10908135
负责人：
Jian Jin
金额：
$ 23.07万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10908135
关键词：
Accounting Acute Lymphocytic Leukemia Acute leukemia Affect Binding Biological Availability CCNE1 gene Cancer Model Cancer Patient Catalytic Domain Cell model Chemicals Chromatin Clinical Complex Development Disease Dissection Dose Drug Kinetics Drug Targeting EP300 gene EZH2 gene Enhancers Exhibits Gene Activation Genes Genetically Engineered Mouse Genomics Goals Histone H3 Histones Homologous Gene Human In Vitro Infant Knock-out Lead Left Leukemic Cell Ligands Link Lysine MLL gene Mediating Modeling Mus Oncogene Activation Oncogenes Oncogenic Oncoproteins Oral Outcome Pathway interactions Patients Phenotype Polycomb Prognosis Property Protac Public Health Publishing Reporting Repression Research Role Series Site Solid Technology Testing Therapeutic Therapeutic Effect Transactivation Xenograft procedure antitumor effect c-myc Genes cancer cell cofactor design drug candidate effective therapy gene repression histone methylation histone methyltransferase improved in vivo inhibitor innovation insight knock-down lead series leukemia neoplastic cell novel novel therapeutic intervention novel therapeutics patient derived xenograft model pediatric acute leukemia recruit response small molecule standard care targeted treatment therapeutic candidate tumor tumorigenesis tumorigenic ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY/ABSTRACT Leukemia patients bearing MLL1 rearrangement generally display very poor prognosis, demanding new treatment strategies. Multiple independent studies have identified EZH2, a histone methyltransferase and catalytic subunit of Polycomb Repressive Complex 2 (PRC2), as an attractive drug target in MLL1-rearranged leukemias. However, the current catalytic inhibitors of EZH2 have limited anti-tumor effect. Our preliminary studies show that EZH2 also binds c-MYC and has a non-canonical function in activation of oncogenes (such as Cyclin E1) in MLL1-rearranged leukemias, which differs from the well-known PRC2:EZH2-driven canonical function related to gene repression. In order to target both canonical and non-canonical oncogenic actions by EZH2, we used the Proteolysis Targeting Chimera (PROTAC) technology to generate novel EZH2 small- molecule degraders including MS177. Our extensive preliminary studies have demonstrated that MS177 effectively degrades both PRC2:EZH2 and non-PRC2 partners of EZH2 (e.g., c-MYC, which binds EZH2 to activate oncogenes), thus suppressing both canonical and non-canonical oncogenic activities of EZH2 in tumor. Importantly, our preliminary results also show that MS177 is superior to all of enzymatic inhibitors of EZH2 in treating MLL1-rearranged leukemias. Thus, we hypothesize that: (1) EZH2 has a less-studied, non- canonical oncogenic function, which acts in parallel with the PRC2:EZH2-dependent one to produce more aggressive tumor phenotypes seen in MLL1-rearranged leukemias; and (2) targeting both canonical and non- canonical activities of EZH2 by PROTACs represents a novel and superior therapeutic strategy to inhibition of EZH2’s enzymatic activity alone. Dissection of the mechanisms underlying EZH2-mediated oncogenesis and development of an optimal EZH2 PROTAC as a drug candidate will have significant impact on improving treatments for MLL1-rearranged leukemia patients. Towards this goal, we will further characterize such a new non-canonical oncogenic role of EZH2 in MLL1-rearranged leukemias (Aim 1a) and define effects of EZH2 PROTACs on suppressing both canonical and non-canonical oncogenic activities of EZH2 (Aim 1b). We will also determine in vitro and vivo therapeutic effects of EZH2 PROTACs by employing multiple independent MLL1-rearranged leukemia models including human/murine cancer cells and patient-derived xenografts (PDX) (Aim 2). Lastly, we will optimize our EZH2 PROTAC leads into a drug candidate (Aim 3). Completion of the proposed research will not only provide novel mechanistic understanding of how MLL1-rearranged leukemias develop, but will also validate an innovative therapeutic strategy and deliver a promising therapeutic candidate for the treatment of affected cancer patients.

项目摘要/摘要带有MLL1重排的白血病患者通常表现出非常差的预后，要求新的预后治疗策略。多个独立研究已经确定了EZH2，一种组蛋白甲基转移酶和 Polycomb抑制复合物2（PRC2）的催化亚基，作为MLL1重新培养的有吸引力的药物靶标白血病。但是，EZH2的当前催化抑制剂的抗肿瘤作用有限。我们的初步研究表明，EZH2还结合了C-MYC，并且在激活癌基因中具有非典型功能（这样作为Cyclin E1）在MLL1重新培训的白血病中，它与众所周知的PRC2：EZH2驱动的规范不同与基因表达有关的功能。为了针对规范和非典型致癌作用 EZH2，我们使用靶向嵌合剂（Protac）技术的蛋白水解来生成新型的EZH2 Small- 分子降解器，包括MS177。我们广泛的初步研究表明MS177 有效地降解Ezh2的Prc2：Ezh2和非PRC2伙伴（例如，C-Myc，将EZH2结合到激活致癌基因），从而抑制EZH2在瘤。重要的是，我们的初步结果还表明，MS177优于所有酶抑制剂 EZH2治疗MLL1重新培养的白血病。这是我们假设的：（1）EZH2的研究较少，非 - 规范的致癌功能，与Prc2：Ezh2依赖性的作用相关，以产生更多在MLL1重建的白血病中看到的侵袭性肿瘤表型；（2）针对规范和非 - Protacs通过EZH2的规范活动代表了一种新颖而优越的治疗策略，用于抑制仅EZH2的酶活性。解剖EZH2介导的肿瘤发生的机制和开发最佳EZH2 Protac作为候选药物将对改善产生重大影响 MLL1重新培养白血病患者的治疗。朝向这个目标，我们将进一步描述如此新的 EZH2在MLL1 rear的白血病（AIM 1A）中的非典型致癌作用（AIM 1A），并定义了EZH2的作用 protacs抑制EZH2的规范和非规范性致癌活性（AIM 1B）。我们将还可以通过使用多个独立 MLL1重新培养的白血病模型，包括人/鼠类癌细胞和患者衍生的Xenographictic（PDX）（目标2）。最后，我们将优化我们的EZH2 Protac导致候选药物（AIM 3）。完成拟议的研究不仅将提供对MLL1重新培养白血病的新机械理解开发但还将验证一种创新的治疗策略，并提供有前途的治疗候选者用于治疗受影响的癌症患者。