Investigating the role of EZH2 as a therapeutic target in colorectal cancers

研究 EZH2 作为结直肠癌治疗靶点的作用

• 批准号: 10362561
• 负责人: Patrick Loi
• 金额: $ 3.45万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10362561
• 关键词: Address; Advanced Malignant Neoplasm; Automobile Driving; BRAF gene; Biological Markers; CRISPR/Cas technology; Cancer Etiology; Cancer cell line; Cell Death; Cell Line; Cells; Cessation of life; ChIP-seq; Chromatin; Clinic; Clinical; Clinical Trials; Closure by clamp; Colorectal Cancer; Combined Modality Therapy; Complex; Data; Databases; Defect; Development; Developmental Gene; Disease; Drug Combinations; Drug Targeting; Drug resistance; EZH2 gene; Encyclopedias; Environment; Epigenetic Process; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Histone H3; Human; In Vitro; Intrinsic factor; KRAS2 gene; Lead; Lymphoma; Lysine; MAP Kinase Gene; MEK inhibition; MEKs; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Methyltransferase; Modeling; Mutation; Oncogenic; Output; Pathway interactions; Patients; Pharmacotherapy; Phosphotransferases; Play; Polycomb; Pre-Clinical Model; Predictive Factor; Refractory; Research; Resistance; Resistance development; Role; Running; Series; Signal Transduction; Solid Neoplasm; Testing; Therapeutic; Translating; Work; Xenograft Model; Xenograft procedure; advanced disease; antitumor agent; base; cancer cell; colon cancer cell line; colorectal cancer treatment; cytotoxic; differential expression; effective therapy; efficacy evaluation; efficacy testing; in vivo; ineffective therapies; inhibitor; insight; interest; malignant breast neoplasm; melanoma; mouse model; mutant; novel; novel strategies; overexpression; patient response; pre-clinical; pre-clinical therapy; predictive marker; prevent; programs; prostate cancer metastasis; small hairpin RNA; targeted agent; targeted treatment; therapeutic target; transcriptome sequencing; tumor

Abstract The Polycomb Repressive Complex 2 (PRC2) is a highly conserved developmental regulator that maintains cellular identity by dynamically silencing key genes involved in differentiation. Alterations in EZH2, the catalytic methyltransferase, have been shown to play a driving role in many cancers. Activating mutations in EZH2 have been detected in a subset of cancers, such as melanoma and lymphomas. However, in most solid tumors, EZH2 is more commonly overexpressed. EZH2 expression levels progressively increase in advanced tumors, and has been functionally shown to drive prostate cancer metastasis. Nevertheless, the role of EZH2 in other solid tumors, including colorectal cancers (CRC) has not been sufficiently explored. Specifically, EZH2 is overexpressed in 78.5% of CRC, and its expression appears to inversely correlate with patient survival. We hypothesized that EZH2 could be an attractive therapeutic target, although its role and targets in CRC are unknown. CRC is the is one of the leading causes of cancer deaths worldwide, and advanced metastatic disease is still incurable. Thus, there is a significant unmet clinical need for treatments for CRC, especially those with activating mutations in KRAS. Many drugs that target classic oncogenic kinases are ineffective therapies as single agents, such as MEK inhibitors for KRAS mutant solid tumors. Therefore, one approach has been to develop more effective combination therapies that might enhance the sensitivity of cells to MEK inhibitors and/or prevent resistance. In a series of studies, our lab began exploring EZH2 inhibitor-based combination therapies in a variety of solid tumors. Interestingly, we have found that EZH2 inhibitors are frequently effective when combined with agents that target other key oncogenic pathways in a given tumor type, such as in breast and prostate cancer. We hypothesize that co-targeting EZH2 along with key oncogenic pathways may lead to cooperative killing of CRC cells by clamping down on crucial oncogenic signals at both the kinase level and the transcriptional level. My preliminary data demonstrate that a combination of EZH2 and MEK inhibitors cooperate to kill KRAS mutant CRC, which reveal a novel approach for treating this advanced disease. I propose to address several essential open-ended questions before translating a combination therapy into the clinic, such as the mechanism of action, the cell intrinsic factors that render tumors responsive to treatment, and whether the drug combination works in an in vivo preclinical and biologically relevant setting. In Aim 1, I propose to identify putative biomarkers that dictate sensitivity to EZH2/MEK inhibitors by conducting genomic analyses between sensitive and resistant cell lines. In Aim 2, I will elucidate the mechanism of action by obtaining a global view of chromatin and gene regulation, and I will identify critical PRC2 target genes that modulated in CRC after combination treatment. In Aim 3, I will test the efficacy of EZH2-based combination therapies in in vivo xenograft models of CRC. Together, these findings will establish a new paradigm for epigenetic-based combination therapies for advanced diseases that are currently untreatable.

摘要 Polycomb Repressive Complex 2（PRC 2）是一种高度保守的发育调节因子， 通过动态沉默参与分化的关键基因来确定细胞的同一性。在EZH 2中的改变， 甲基转移酶，已经显示在许多癌症中起驱动作用。EZH 2中的激活突变具有 在癌症的一个子集中被检测到，例如黑色素瘤和淋巴瘤。然而，在大多数实体瘤中，EZH 2 通常是过度表达。EZH 2表达水平在晚期肿瘤中逐渐增加， 在功能上被证明是前列腺癌转移的驱动因素。然而，EZH 2在其他固体中的作用 包括结肠直肠癌（CRC）在内的肿瘤的治疗尚未得到充分的探索。具体地，EZH 2是 在78.5%的CRC中过表达，并且其表达似乎与患者存活率呈负相关。我们 假设EZH 2可能是一个有吸引力的治疗靶点，尽管它在CRC中的作用和靶点是 未知CRC是全球癌症死亡的主要原因之一，并且是晚期转移性疾病 仍然无法治愈因此，对于CRC的治疗存在显著的未满足的临床需求，尤其是那些具有以下特征的患者： 激活KRAS突变。许多靶向经典致癌激酶的药物是无效的疗法， 单药，如用于KRAS突变实体瘤的MEK抑制剂。因此，一种方法是 开发可能增强细胞对MEK抑制剂的敏感性的更有效的联合疗法，和/或 防止抵抗。在一系列的研究中，我们的实验室开始探索基于EZH 2转运蛋白的联合疗法， 在各种实体瘤中。有趣的是，我们发现EZH 2抑制剂在以下情况下通常是有效的： 与靶向给定肿瘤类型（例如乳腺癌）中的其它关键致癌途径的药剂组合， 前列腺癌我们假设，共靶向EZH 2沿着关键致癌通路可能导致 通过在激酶水平和细胞周期水平上抑制关键的致癌信号， 转录水平。我的初步数据表明，EZH 2和MEK抑制剂的组合 杀死KRAS突变型CRC，这揭示了治疗这种晚期疾病的新方法。我提议 在将联合治疗转化为临床之前，需要回答几个基本的开放式问题，例如 作用机制，使肿瘤对治疗有反应的细胞内在因素，以及药物是否 组合在体内临床前和生物学相关环境中起作用。在目标1中，我建议确定假定的 通过在敏感的EZH 2/MEK抑制剂之间进行基因组分析来决定对EZH 2/MEK抑制剂的敏感性的生物标志物 和抗性细胞系。在目标2中，我将通过获得染色质的全局视图来阐明作用机制 和基因调控，我将确定关键PRC 2的靶基因，在CRC联合后调制 治疗在目标3中，我将测试基于EZH 2的组合疗法在体内异种移植物模型中的功效。 《儿童权利公约》。总之，这些发现将为基于表观遗传学的联合治疗建立一个新的范例， 目前无法治愈的晚期疾病。