Dissecting and targeting canonical and non-canonical oncogenic functions of EZH2 in cancer
Dissecting and targeting canonical and non-canonical oncogenic functions of EZH2 in cancer
批准号:
10544005
负责人:
Jian Jin
金额:
$47.93万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-01-01 至 2023-07-31
关键词:
AccountingAcute Lymphocytic LeukemiaAcute leukemiaAffectBindingBiological AvailabilityCCNE1 geneCancer ModelCancer PatientCatalytic DomainCell modelChemicalsChromatinClinicalComplexDevelopmentDiseaseDissectionDoseDrug KineticsDrug TargetingEP300 geneEZH2 geneEnhancersExhibitsGene ActivationGenesGenetically Engineered MouseGenomicsGoalsHistone H3HistonesHomologous GeneHumanIn VitroInfantKnock-outLeadLeftLeukemic CellLigandsLinkLysineMLL geneMalignant NeoplasmsMediatingModelingMusOncogene ActivationOncogenesOncogenicOncoproteinsOralOutcomePathway interactionsPatientsPhenotypePolycombPrognosisPropertyProtacPublic HealthPublishingReportingRepressionResearchRoleSeriesSiteSolidTechnologyTestingTherapeuticTherapeutic EffectTransactivationXenograft procedureantitumor effectc-myc Genescancer cellcofactordesigndrug candidateeffective therapygene repressionhistone methylationhistone methyltransferaseimprovedin vivoinhibitorinnovationinsightknock-downlead seriesleukemianeoplastic cellnovelnovel therapeutic interventionnovel therapeuticspatient derived xenograft modelpediatric acute leukemiarecruitresponsesmall moleculestandard caretargeted treatmenttherapeutic candidatetumortumorigenesistumorigenicubiquitin-protein ligase
中文摘要
项目概要/摘要
携带MLL1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EZH2,一种组蛋白甲基转移酶,
多梳抑制复合物2(PRC2)的催化亚基,作为MLL1重排中有吸引力的药物靶点,
白血病然而,目前EZH2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EZH2也结合c-MYC,并在癌基因(如
作为细胞周期蛋白E1)在MLL1重排的白血病,这不同于众所周知的PRC2:EZH2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,
EZH2,我们使用蛋白水解靶向嵌合体(PROTAC)技术来产生新的EZH2小-
分子降解剂,包括MS177。我们广泛的初步研究表明,MS177
有效地降解PRC2:EZH2和EZH2的非PRC2配偶体(例如,c-MYC,其结合EZH2,
激活致癌基因),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,MS 177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具有较少研究的,非-
典型的致癌功能,与PRC2:EZH2依赖性功能平行发挥作用,产生更多的
MLL1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EZH2的典型活性代表了一种新的和上级的治疗策略,
EZH2单独的酶活性。EZH2介导的肿瘤发生机制的剖析,
作为候选药物的最佳EZH2 PROTAC的开发将对改善
MLL1重排白血病患者的治疗。为了实现这一目标,我们将进一步描述这样一个新的
EZH2在MLL1重排白血病(Aim 1a)中的非典型致癌作用,并确定EZH2的作用
PROTAC抑制EZH2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EZH2 PROTAC的体外和体内治疗效果,
MLL1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)。最后,我们将优化我们的EZH2 PROTAC导致成为候选药物(目标3)。完成
拟议的研究不仅将提供MLL1重排白血病如何在白血病细胞中表达的新的机制理解,
开发,但也将验证创新的治疗策略,并提供有前途的治疗候选人
用于治疗癌症患者。
英文摘要
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.
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