Characterizing and Targeting CHD4 Deficiency in Endometrial Cancer

子宫内膜癌中 CHD4 缺陷的特征和靶向治疗

基本信息

批准号：
8610904
负责人：
Shiaw-Yih Lin
金额：
$ 31.93万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8610904
关键词：
American BRCA1 gene Cancer Patient Cancer cell line Carcinoma Catalytic Domain Cell Culture Techniques Cells Clinic Clinical Collection Complex DNA Damage DNA Repair DNA-Binding Proteins Data Databases Development Diagnostic Neoplasm Staging Doxorubicin Endometrial Endometrial Carcinoma Endometrial Neoplasms Etiology Exhibits Gene Deletion Genes Genetic Genome Stability Genomic Instability Genomics Investigation Knockout Mice Link Maintenance Malignant Neoplasms Modeling Molecular Mus Mutate Mutation NuRD complex Outcome Paclitaxel Papillary Patients Pharmaceutical Preparations Play Poly(ADP-ribose) Polymerases Progesterone Receptors Radiation Radiation therapy Recurrence Role Sampling Serous Specificity Specimen Testing The Cancer Genome Atlas Tissues Transcription Repressor/Corepressor Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Tumor stage Woman base cancer cell cancer initiation cancer therapy chemotherapy driving force female reproductive system helicase homologous recombination inhibitor/antagonist mortality mouse model novel public health relevance recombinational repair response therapeutic target tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Endometrial cancer is one of the most common cancers of the female reproductive system among American women. For patients with localized low-grade endometrioid endometrial carcinoma (EEC), mortality is low. However, for patients with metastatic or recurrent EEC or nonendometrioid carcinomas, such as the aggressive uterine papillary serous carcinoma (UPSC), treatment options are limited, and outcomes are abysmal. Thus, it is critical to identify key gene aberrations in endometrial cancer for development of novel effective targeted therapy. Through analyzing gene sequencing data from The Cancer Genome Atlas, we have found a high rate of mutation of CHD4 in endometrial cancer (15% in EEC and 35% in UPSC). This high CHD4 mutation rate was not seen in other tumor types, suggesting that CHD4 aberrations are a critical driver of endometrial cancer development. In addition, we found that CHD4 expression was significantly reduced in many endometrial cancer cell lines, suggesting that CHD4 may function as a novel tumor suppressor gene and a potential therapeutic target for endometrial cancer. Recently, increasing evidence has shown that an intact DNA damage response (DDR) is essential for maintenance of genomic stability and acts as a critical barrier to cancer development. Interestingly, we have recently identified a critical role of CHD4 in DDR, particularly in homologous recombination (HR) repair. Notably, we demonstrated that CHD4 with mutations seen in endometrial cancer patients lacked HR repair function, suggesting a critical link between the DDR function of CHD4 and endometrial cancer suppression. In our preliminary studies, we also found that CHD4-deficient endometrial cancer cells were more sensitive to PARP (poly[ADP-ribose] polymerase) inhibitors because of their defective HR repair. All of these intriguing results strongly suggest that CHD4 functions as a novel tumor suppressor for endometrial cancer and that targeting CHD4 deficiency using PARP inhibitors constitutes an effective targeted therapy for CHD4-deficient endometrial cancer. Three specific aims are proposed to test this hypothesis: (1) To assess clinical endometrial cancer tissue specimens for CHD4 aberrations and determine whether CHD4 deficiency is correlated with tumor grade, tumor stage, cancer subtype, and patient survival. (2) To determine whether loss of CHD4 contributes to endometrial cancer development using our CHD4 conditional knockout mouse model. These models will provide genetic evidence for CHD4 deficiency as a driving force for endometrial cancer development. (3) To develop a novel treatment for CHD4-deficient endometrial cancer using a synthetic lethality approach. We will assess the response of CHD4-deficient cells to potent PARP inhibitors in cell culture and in the mouse models. We will also combine PARP inhibitors with radiation and with doxorubicin or paclitaxel to establish optimal therapies. In summary, this project will not only help reveal novel molecular therapeutic targets for endometrial cancer but also have immediate clinical impact by establishing a new treatment based on targeting CHD4-deficient endometrial cancer with PARP inhibitors.

描述（由申请人提供）：子宫内膜癌是美国女性中最常见的女性生殖系统癌症之一。对于局限性低级别子宫内膜样子宫内膜癌 (EEC) 患者，死亡率较低。然而，对于患有转移性或复发性 EEC 或非子宫内膜样癌（例如侵袭性子宫乳头状浆液性癌 (UPSC)）的患者，治疗选择有限，而且结果很糟糕。因此，确定子宫内膜癌的关键基因畸变对于开发新型有效的靶向治疗至关重要。通过分析癌症基因组图谱的基因测序数据，我们发现子宫内膜癌中 CHD4 突变率很高（EEC 中为 15%，UPSC 中为 35%）。这种高 CHD4 突变率在其他肿瘤类型中未见，表明 CHD4 畸变是子宫内膜癌发展的关键驱动因素。此外，我们发现CHD4表达在许多子宫内膜癌细胞系中显着降低，表明CHD4可能作为一种新型抑癌基因和子宫内膜癌的潜在治疗靶点。最近，越来越多的证据表明，完整的 DNA 损伤反应 (DDR) 对于维持基因组稳定性至关重要，并且是癌症发展的关键障碍。有趣的是，我们最近发现了 CHD4 在 DDR 中的关键作用，特别是在同源重组 (HR) 修复中。值得注意的是，我们证明了子宫内膜癌患者中出现突变的 CHD4 缺乏 HR 修复功能，这表明 CHD4 的 DDR 功能与子宫内膜癌抑制之间存在关键联系。在我们的初步研究中，我们还发现CHD4缺陷的子宫内膜癌细胞由于其HR修复缺陷而对PARP（聚[ADP-核糖]聚合酶）抑制剂更敏感。所有这些有趣的结果强烈表明，CHD4 作为子宫内膜癌的新型肿瘤抑制因子发挥作用，并且使用 PARP 抑制剂针对 CHD4 缺陷构成了针对 CHD4 缺陷型子宫内膜癌的有效靶向治疗。提出了三个具体目标来检验这一假设：（1）评估临床子宫内膜癌组织标本的CHD4畸变，并确定CHD4缺乏是否与肿瘤分级、肿瘤分期、癌症亚型和患者生存相关。 (2) 使用我们的 CHD4 条件敲除小鼠模型来确定 CHD4 的缺失是否会导致子宫内膜癌的发展。这些模型将为 CHD4 缺陷作为子宫内膜癌发展的驱动力提供遗传证据。 (3) 使用合成致死方法开发一种治疗 CHD4 缺陷型子宫内膜癌的新疗法。我们将在细胞培养物和小鼠模型中评估 CHD4 缺陷细胞对强效 PARP 抑制剂的反应。我们还将 PARP 抑制剂与放射疗法以及阿霉素或紫杉醇结合起来，以建立最佳疗法。总之，该项目不仅有助于揭示子宫内膜癌的新分子治疗靶点，而且通过建立一种基于 PARP 抑制剂靶向 CHD4 缺陷型子宫内膜癌的新疗法，具有直接的临床影响。