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

• 批准号: 8792837
• 负责人: Shiaw-Yih Lin
• 金额: $ 32.3万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792837
• 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; Health; 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; genome integrity; helicase; homologous recombination; inhibitor/antagonist; mortality; mouse model; novel; recombinational repair; response; targeted cancer therapy; targeted treatment; therapeutic target; tumor; tumor progression

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生殖系统最常见的癌症之一。对于局部低级别子宫内膜样子宫内膜癌（EEC）患者，死亡率很低。然而，对于转移性或复发性EEC或非子宫内膜样癌（如侵袭性子宫乳头状浆液性癌（UPSC））的患者，治疗选择有限，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的有效的靶向治疗方法至关重要。通过分析来自The Cancer Genome Atlas的基因测序数据，我们发现CHD4在子宫内膜癌中的突变率很高（EEC为15%，UPSC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在许多子宫内膜癌细胞系中的表达显著降低，提示CHD4可能作为一种新的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屏障。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，我们证明了在子宫内膜癌患者中发现的突变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对PARP（聚[adp核糖]聚合酶）抑制剂更敏感，因为它们的HR修复缺陷。所有这些有趣的结果强烈表明，CHD4作为一种新的子宫内膜癌肿瘤抑制因子，使用PARP抑制剂靶向CHD4缺陷是治疗CHD4缺陷子宫内膜癌的有效靶向治疗方法。为了验证这一假设，我们提出了三个具体目的：(1)评估临床子宫内膜癌组织标本中CHD4的畸变，确定CHD4缺失是否与肿瘤分级、肿瘤分期、癌症亚型和患者生存相关。(2)通过我们的CHD4条件敲除小鼠模型来确定CHD4的缺失是否有助于子宫内膜癌的发展。这些模型将为CHD4缺乏作为子宫内膜癌发展的驱动力提供遗传证据。(3)利用合成致死性方法研究治疗chd4缺陷子宫内膜癌的新方法。我们将在细胞培养和小鼠模型中评估chd4缺陷细胞对强效PARP抑制剂的反应。我们还将把PARP抑制剂与放疗、阿霉素或紫杉醇联合使用，以建立最佳治疗方法。综上所述，本项目不仅有助于揭示子宫内膜癌新的分子治疗靶点，而且通过PARP抑制剂靶向chd4缺陷子宫内膜癌建立新的治疗方法，具有直接的临床影响。