Mechanisms of radioresistance and strategies for radiosensitization in ovarian clear cell carcinoma

卵巢透明细胞癌的放射抵抗机制及放射增敏策略

• 批准号: 10446186
• 负责人: Guang Peng
• 金额: $ 38.65万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-16 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446186
• 关键词: ARID1A gene; Animal Model; Biochemistry; Bioinformatics; Biology; CRISPR/Cas technology; Cells; Cellular biology; Chromatin Remodeling Factor; Cytosine; DNA; DNA Damage; DNA Methylation; DNA Repair; DNA Sequence; Data; Double-Stranded RNA; Elements; Frequencies; Gene Silencing; Genes; Genetic; Genetic Transcription; Genetic study; Goals; Heterochromatin; Immune; Immunotherapy; Impairment; Innate Immune Response; Interferons; Ionizing radiation; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Molecular; Mutate; Mutation; Nucleic Acids; Ovarian Carcinoma; Ovarian Clear Cell Tumor; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Proteomics; RNA; Radiation; Radiation Induced DNA Damage; Radiation exposure; Radiation therapy; Radiosensitization; Regimen; Repression; Research; Role; SWI/SNF Family Complex; Sampling; Satellite DNA; Serine; Signal Transduction; Site; Stimulator of Interferon Genes; Testing; Therapeutic; Transferase; Translating; Tumor Immunity; base; cancer cell; cancer genomics; clinical application; effective therapy; genomic data; heterochromatin-specific nonhistone chromosomal protein HP-1; improved; in vivo; inhibitor; innate immune sensing; innovation; interdisciplinary approach; novel therapeutics; ovarian neoplasm; pre-clinical; programs; radiation resistance; recruit; response; small hairpin RNA; therapeutically effective; translational study; tumor

DESCRIPTION Ovarian clear-cell carcinoma (OCCC) is the second most common type of ovarian cancer and is associated with poor survival because of the lack of effective therapeutic options. Our long-term goal is to understand the molecular mechanisms that create therapeutic opportunities in OCCC and to translate such discoveries into meaningful clinical applications. ARID1A, a component of the chromatin remodeling complex SWI/SNF, is mutated in more than 50% of OCCC. With the support of our current R01 project, we have established a successful research program to study the role of the ARID1A-SWI/SNF complex in regulating the DNA damage response (DDR) and DNA repair. In the preliminary studies leading to this renewal application, we discovered a new role for the ARID1A-SWI/SNF complex in transcriptional silencing of heterochromatin repetitive DNA sequences, namely satellite DNA element (satDNA) in response to ionizing radiation (IR)-induced DNA damage. We also showed that aberrant IR-induced satRNA expression activates RNA-sensing innate immune response in ARID1A-deficient cells. These exciting and promising findings have led us to hypothesize that ARID1A deficiency unleashes IR- induced de-repression of heterochromatin repetitive satDNA sequences by impairing DNMT3A-mediated DNA methylation and transcriptional silencing. This consequently activates the dsRNA-sensing RIG-1/MDA5 pathway, and provides the rationale to use ATM inhibitors to enhance the efficacy of radiotherapy and immunotherapy by selectively modulating nucleic acid-mediated innate immune response in ARID1A-deficient tumors. We will employ multidisciplinary approaches, including molecular/biochemistry/cell biology-based mechanistic studies, shRNA/CRISPR-Cas9-based genetic studies, bioinformatic analysis and preclinical animal model-based translational studies, and analysis of OCCC patient samples to test this hypothesis. Together, our proposed project will not only mechanistically advance our fundamental understanding of the underlying biology of how the ARID1A-SWI/SNF chromatin remodeling complex maintains heterochromatin transcriptional silencing to radiation-induced DNA damage, but will also develop new personalized immune- based radiotherapy regimens tailored to the genetic contexts of tumors, such as ARID1A deficiency or more broadly SWI/SNF-mutated cancers.

描述 卵巢透明细胞癌 (OCCC) 是第二常见的卵巢癌类型，与 由于缺乏有效的治疗选择，生存率很低。我们的长期目标是了解 为 OCCC 创造治疗机会并将这些发现转化为分子机制 有意义的临床应用。 ARID1A 是染色质重塑复合体 SWI/SNF 的一个组成部分，在超过 50% 的 OCCC 中发生突变。 在我们当前的 R01 项目的支持下，我们已经建立了一个成功的研究计划来研究 ARID1A-SWI/SNF 复合物在调节 DNA 损伤反应 (DDR) 和 DNA 修复中的作用。在 在这次更新申请的初步研究中，我们发现了 ARID1A-SWI/SNF 的新作用 异染色质重复 DNA 序列（即卫星 DNA）转录沉默的复合体 元素 (satDNA) 响应电离辐射 (IR) 引起的 DNA 损伤。我们还表明，异常 IR 诱导的 satRNA 表达可激活 ARID1A 缺陷细胞中 RNA 感应先天免疫反应。 这些令人兴奋和有希望的发现使我们假设 ARID1A 缺陷会释放 IR- 通过损害 DNMT3A 介导的 DNA 诱导异染色质重复 satDNA 序列的去抑制 甲基化和转录沉默。这因此激活了 dsRNA 感应 RIG-1/MDA5 途径，并提供了使用 ATM 抑制剂增强放疗疗效的基本原理 通过选择性调节 ARID1A 缺陷的核酸介导的先天免疫反应进行免疫治疗 肿瘤。我们将采用多学科方法，包括基于分子/生物化学/细胞生物学的方法 机制研究、基于shRNA/CRISPR-Cas9的遗传学研究、生物信息学分析和临床前 基于动物模型的转化研究，以及对 OCCC 患者样本的分析来检验这一假设。 总之，我们提出的项目不仅会机械地推进我们对 ARID1A-SWI/SNF 染色质重塑复合物如何维持异染色质的基础生物学 转录沉默对辐射引起的 DNA 损伤的影响，但也将开发新的个性化免疫 针对肿瘤遗传背景（例如 ARID1A 缺陷或更多）量身定制的放射治疗方案 广泛 SWI/SNF 突变的癌症。