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:
  • 金额:
    $ 23.07万
  • 依托单位:
  • 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

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 携带MLL1重排的白血病患者通常表现出非常差的预后,需要新的 治疗策略。多项独立研究已确定EZH2,一种组蛋白甲基转移酶和 多梳抑制复合体2的催化亚基作为MLL1重排的诱人药物靶点 白血病。然而,目前EZH2的催化抑制剂抗肿瘤作用有限。我们的预赛 研究表明,EZH2还与c-myc结合,并在癌基因(如 在MLL1重排的白血病中,它不同于众所周知的PRC2:EZH2驱动的规范 与基因抑制相关的功能。为了同时针对规范和非规范致癌作用,通过 EZH2,我们利用蛋白质水解靶向嵌合体(PROTAC)技术产生了新型的EZH2小分子- 分子降解剂包括MS177。我们广泛的初步研究表明,MS177 有效地降低PRC2:EZH2和EZH2的非PRC2合作伙伴(例如,将EZH2绑定到 激活癌基因),从而抑制EZH2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,MS177优于所有的酶抑制剂 EZH2治疗MLL1重排白血病因此,我们假设:(1)EZH2具有一个较少研究的、非 规范致癌功能,与PRC2并行作用:依赖于EZH2的功能产生更多 MLL1重排白血病中的侵袭性肿瘤表型;以及(2)针对典型和非典型性白血病 PROTACs对EZH2的规范活性代表了一种新的、优越的治疗策略 鄂州医科大学硕士学位论文S单独酶活。EZH2介导的肿瘤发生和发展机制的剖析 作为候选药物的最佳EZH2 PROTAC的开发将对改进 MLL1重排白血病患者的治疗。为了实现这一目标,我们将进一步表征这样一个新的 EZH2在MLL1重排白血病中的非典型致癌作用(目标1a)及确定EZH2的作用 抑制EZH2的典型和非典型致癌活性的PROTAC(目标1b)。我们会 用多个独立的方法测定EZH2 PROTACs的体内外治疗效果 包括人/鼠癌细胞和患者来源的异种移植(PDX)的MLL1重排白血病模型 (目标2)。最后,我们将优化我们的EZH2 PROTAC线索,使其成为候选药物(目标3)。已完成的 拟议中的研究不仅将为MLL1重排白血病如何发生提供新的机制理解 开发,但也将验证创新的治疗策略并提供有前景的候选治疗方案 用于治疗受影响的癌症患者。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Jian Jin其他文献

Jian Jin的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Jian Jin', 18)}}的其他基金

Novel Inhibitors of Lysine Methyltransferases G9a and GLP for the Treatment of Alzheimer's Disease
用于治疗阿尔茨海默病的新型赖氨酸甲基转移酶 G9a 和 GLP 抑制剂
  • 批准号:
    10752812
  • 财政年份:
    2023
  • 资助金额:
    $ 23.07万
  • 项目类别:
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:
    10544005
  • 财政年份:
    2022
  • 资助金额:
    $ 23.07万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 23.07万
  • 项目类别:
Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias
发现一流的 WDR5 PROTAC 作为 MLL 重排白血病的新型治疗策略
  • 批准号:
    10712396
  • 财政年份:
    2022
  • 资助金额:
    $ 23.07万
  • 项目类别:
Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias
发现一流的 WDR5 PROTAC 作为 MLL 重排白血病的新型治疗策略
  • 批准号:
    10387368
  • 财政年份:
    2022
  • 资助金额:
    $ 23.07万
  • 项目类别:
Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias
发现一流的 WDR5 PROTAC 作为 MLL 重排白血病的新型治疗策略
  • 批准号:
    10615610
  • 财政年份:
    2022
  • 资助金额:
    $ 23.07万
  • 项目类别:
Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias
发现一流的 WDR5 PROTAC 作为 MLL 重排白血病的新型治疗策略
  • 批准号:
    10745902
  • 财政年份:
    2022
  • 资助金额:
    $ 23.07万
  • 项目类别:
Development of Novel PROTACs Targeting the ENL YEATS Domain for Treating MLL-rearranged Leukemias
开发针对 ENL YEATS 结构域的新型 PROTAC,用于治疗 MLL 重排白血病
  • 批准号:
    10222062
  • 财政年份:
    2021
  • 资助金额:
    $ 23.07万
  • 项目类别:
Development of Novel PROTACs Targeting the ENL YEATS Domain for Treating MLL-rearranged Leukemias
开发针对 ENL YEATS 结构域的新型 PROTAC,用于治疗 MLL 重排白血病
  • 批准号:
    10372195
  • 财政年份:
    2021
  • 资助金额:
    $ 23.07万
  • 项目类别:
Development of Novel PROTACs Targeting the ENL YEATS Domain for Treating MLL-rearranged Leukemias
开发针对 ENL YEATS 结构域的新型 PROTAC,用于治疗 MLL 重排白血病
  • 批准号:
    10616478
  • 财政年份:
    2021
  • 资助金额:
    $ 23.07万
  • 项目类别:

相似海外基金

Understanding of the onset and recurrence pattern of intractable acute lymphocytic leukemia based on clone analysis
基于克隆分析了解难治性急性淋巴细胞白血病的发病和复发模式
  • 批准号:
    20K08723
  • 财政年份:
    2020
  • 资助金额:
    $ 23.07万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Novel Inhibitors of Multi-Drug-Resistant Mutants of BCR-ABL for the Treatment of Chronic Myelogenous Leukemia (CML) and Ph Positive Acute Lymphocytic Leukemia (ALL).
BCR-ABL 多重耐药突变体的新型抑制剂,用于治疗慢性粒细胞白血病 (CML) 和 Ph 阳性急性淋巴细胞白血病 (ALL)。
  • 批准号:
    9047400
  • 财政年份:
    2015
  • 资助金额:
    $ 23.07万
  • 项目类别:
The Role of Genetic Variants in Sensitivity to Methotrexate in Acute Lymphocytic Leukemia Survivors
遗传变异在急性淋巴细胞白血病幸存者对甲氨蝶呤敏感性中的作用
  • 批准号:
    319114
  • 财政年份:
    2014
  • 资助金额:
    $ 23.07万
  • 项目类别:
    Fellowship Programs
Targeting the Bone Marrow Microenvironment In Acute Lymphocytic Leukemia
针对急性淋巴细胞白血病的骨髓微环境
  • 批准号:
    8595788
  • 财政年份:
    2013
  • 资助金额:
    $ 23.07万
  • 项目类别:
Targeting hypoxic microenvironment in Acute Lymphocytic Leukemia
针对急性淋巴细胞白血病的缺氧微环境
  • 批准号:
    8023518
  • 财政年份:
    2011
  • 资助金额:
    $ 23.07万
  • 项目类别:
Targeting hypoxic microenvironment in Acute Lymphocytic Leukemia
针对急性淋巴细胞白血病的缺氧微环境
  • 批准号:
    8404025
  • 财政年份:
    2011
  • 资助金额:
    $ 23.07万
  • 项目类别:
Targeting hypoxic microenvironment in Acute Lymphocytic Leukemia
针对急性淋巴细胞白血病的缺氧微环境
  • 批准号:
    8220724
  • 财政年份:
    2011
  • 资助金额:
    $ 23.07万
  • 项目类别:
Targeting hypoxic microenvironment in Acute Lymphocytic Leukemia
针对急性淋巴细胞白血病的缺氧微环境
  • 批准号:
    8599754
  • 财政年份:
    2011
  • 资助金额:
    $ 23.07万
  • 项目类别:
INSULIN RESISTANCE IN CHILDREN WITH ACUTE LYMPHOCYTIC LEUKEMIA UNDERGOING INDUCT
正在接受治疗的急性淋巴细胞白血病儿童的胰岛素抵抗
  • 批准号:
    8356701
  • 财政年份:
    2010
  • 资助金额:
    $ 23.07万
  • 项目类别:
INSULIN RESISTANCE IN CHILDREN WITH ACUTE LYMPHOCYTIC LEUKEMIA UNDERGOING INDUCT
正在接受治疗的急性淋巴细胞白血病儿童的胰岛素抵抗
  • 批准号:
    8166720
  • 财政年份:
    2009
  • 资助金额:
    $ 23.07万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了