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

描述 卵巢透明细胞癌（OCCC）是第二种最常见的卵巢癌类型，与卵巢癌相关。 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 在OCCC中创造治疗机会的分子机制，并将这些发现转化为 有意义的临床应用。 ARID 1A是染色质重塑复合物SWI/SNF的一个组成部分，在超过50%的OCCC中发生突变。 在我们目前的R 01项目的支持下，我们已经建立了一个成功的研究计划， ARID 1A-SWI/SNF复合物在调节DNA损伤反应（DDR）和DNA修复中的作用。在 通过对这次更新申请的初步研究，我们发现了ARID 1A-SWI/SNF的一个新作用 异染色质重复DNA序列（即卫星DNA）的转录沉默复合体 分子（satDNA）对电离辐射（IR）诱导的DNA损伤的反应。我们还发现， IR诱导的satRNA表达激活ARID 1A缺陷细胞中的RNA感应先天免疫应答。 这些令人兴奋和有希望的发现使我们假设ARID 1A缺陷会释放IR- 通过损害DNMT 3A介导的DNA诱导异染色质重复satDNA序列的去阻遏 甲基化和转录沉默。这因此激活dsRNA敏感RIG-1/MDA 5 途径，并提供了使用ATM抑制剂，以提高放射治疗的疗效， 通过选择性调节ARID 1A缺陷型小鼠中核酸介导的先天性免疫应答的免疫疗法 肿瘤的我们将采用多学科的方法，包括分子/生物化学/细胞生物学为基础的 机制研究，基于shRNA/CRISPR-Cas9的遗传研究，生物信息学分析和临床前研究 基于动物模型的转化研究，以及OCCC患者样本的分析，以检验这一假设。 总之，我们提出的项目不仅将在机械上推进我们对生物多样性的基本理解， ARID 1A-SWI/SNF染色质重塑复合物如何维持异染色质的基础生物学 转录沉默对辐射诱导的DNA损伤，但也将开发新的个性化免疫- 根据肿瘤的遗传背景定制的基于放射治疗的方案，例如ARID 1A缺陷或更多 广泛SWI/SNF突变的癌症。

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.