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

剖析和靶向 EZH2 在癌症中的典型和非典型致癌功能

• 批准号: 10389877
• 负责人: Jian Jin
• 金额: $ 64.4万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/10389877
• 关键词: Accounting; Acute; 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; Malignant Neoplasms; Mediating; Modeling; Mus; Oncogene Activation; Oncogenes; Oncogenic; Oncoproteins; Oral; Outcome; Pathway interactions; Patients; Phenotype; Polycomb; Prognosis; Property; Protac; Public Health; Publishing; Reporting; Research; Role; Series; Site; Solid; Technology; Testing; Therapeutic; Therapeutic Effect; Transactivation; Xenograft procedure; antitumor effect; base; 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; treatment strategy; tumor; tumorigenesis; tumorigenic; ubiquitin-protein ligase

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 携带MLL 1重排的白血病患者通常显示非常差的预后，需要新的治疗方案。 治疗策略。多项独立研究已经鉴定了EZH 2，一种组蛋白甲基转移酶， 多梳抑制复合物2（PRC 2）的催化亚基，作为MLL 1重排中有吸引力的药物靶点， 白血病然而，目前EZH 2的催化抑制剂具有有限的抗肿瘤作用。我们的初步 研究表明EZH 2也结合c-MYC，并在癌基因（如 作为细胞周期蛋白E1）在MLL 1重排的白血病，这不同于众所周知的PRC 2：EZH 2驱动的典型 与基因阻遏有关的功能。为了靶向典型和非典型致癌作用， EZH 2，我们使用蛋白水解靶向嵌合体（PROTAC）技术来产生新的EZH 2小- 分子降解剂，包括MS 177。我们广泛的初步研究表明，MS 177 有效降解PRC 2：EZH 2和EZH 2的非PRC 2伙伴（例如，c-MYC，其结合EZH 2， 激活致癌基因），从而抑制EZH 2的典型和非典型致癌活性。 肿瘤重要的是，我们的初步结果还表明，MS 177上级所有的酶抑制剂， EZH 2治疗MLL 1重排白血病因此，我们假设：（1）EZH 2具有较少研究的，非- 典型的致癌功能，与PRC 2：EZH 2依赖性功能平行发挥作用，产生更多的 MLL 1重排白血病中观察到的侵袭性肿瘤表型;和（2）靶向典型和非典型白血病 PROTAC对EZH 2的典型活性代表了一种新的和上级的治疗策略， EZH 2单独的酶活性。EZH 2介导的肿瘤发生机制的剖析， 作为候选药物的最佳EZH 2 PROTAC的开发将对改善 MLL 1重排白血病患者的治疗。为了实现这一目标，我们将进一步描述这样一个新的 EZH 2在MLL 1重排白血病（Aim 1a）中的非典型致癌作用，并确定EZH 2的作用 PROTAC抑制EZH 2的典型和非典型致癌活性（目的1b）。我们将 还通过采用多个独立的方法测定EZH 2 PROTAC的体外和体内治疗效果， MLL 1重排白血病模型，包括人/鼠癌细胞和患者来源的异种移植物（PDX） (Aim 2）的情况。最后，我们将优化我们的EZH 2 PROTAC导致成为候选药物（目标3）。完成 拟议的研究不仅提供了MLL 1重排白血病如何在白血病细胞中表达的新机制， 开发，但也将验证创新的治疗策略，并提供有前途的治疗候选人 用于治疗癌症患者。