Mechanisms of radioresistance and strategies for radiosensitization in OCCC

OCCC 的放射抵抗机制和放射增敏策略

• 批准号: 10218064
• 负责人: Guang Peng
• 金额: $ 36.58万
• 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: 2016-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218064
• 关键词: ARID1A gene; Animal Model; Biochemistry; Biological Markers; CHEK1 gene; CHEK2 gene; CRISPR/Cas technology; Cancer Patient; Cell Culture Techniques; Cell Cycle Checkpoint; Cellular biology; Chromatin Remodeling Factor; Combined Modality Therapy; DNA Damage; DNA Repair; DNA damage checkpoint; Data; Development; Exhibits; Frequencies; Genes; Genetic; Genetic study; Genomics; Goals; Immune checkpoint inhibitor; Impairment; In Vitro; Knowledge; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Molecular; Mutate; Mutation; Outcome; Ovarian Carcinoma; Ovarian Clear Cell Tumor; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphotransferases; Platinum; Proteins; Proteomics; Radiation; Radiation Induced DNA Damage; Radiation therapy; Radiosensitization; Regulation; Resistance; Role; SWI/SNF Family Complex; Sampling; Signal Transduction; Testing; Therapeutic; Translating; Treatment Efficacy; Treatment outcome; Ubiquitination; Up-Regulation; base; cancer cell; cancer genomics; chemotherapy; clinical application; functional genomics; genomic data; improved; in vivo; inhibitor/antagonist; innovation; insight; interdisciplinary approach; mutant; mutational status; new therapeutic target; novel; novel therapeutics; ovarian neoplasm; patient biomarkers; patient stratification; radiation resistance; radiation response; response; targeted treatment; therapy resistant; translational study; treatment response; tumor; tumor growth; ubiquitin-protein ligase

DESCRIPTION Ovarian clear-cell carcinoma (OCCC) is the second most common type of ovarian carcinoma. Unlike other types of ovarian carcinoma, OCCC does not respond to standard DNA damage-inducing treatment, including platinum-based chemotherapy and radiotherapy. Ovarian cancer patients in general have poor survival. Because of the lack of efficacy of treatment, the overall survival of patients with advanced OCCC is significantly shorter than that of patients with other types of ovarian carcinoma. Our long-term goal is to understand the molecular mechanisms of treatment resistance in OCCC and to translate such discoveries into meaningful clinical applications. Recent genomic studies have revealed that ARID1A, a component of chromatin remodeling complex SWI/SNF, is the most frequently mutated gene in OCCC. We discovered a novel ubiquitination-dependent role of ARID1A in response to radiation-induced DNA damage. The objective of this application is to determine how ARID1A deficiency leads to aberrant DNA damage checkpoint through ubiquitination regulation and whether we can improve DNA damage-inducing treatment in OCCC by targeting ARID1A deficiency. Our extensive preliminary data support the central hypothesis of our proposal: that ARID1A deficiency promotes adaptive checkpoint response via loss of ARID1A's previously unknown E3-ligase/ubiquitination activity targeting checkpoint protein CHK2, which creates therapeutic opportunities based on checkpoint inhibitors in the context of impaired ATR-CHK1 checkpoint signaling in ARID1A-mutant cancers. We will employ multidisciplinary approaches, including biochemistry-based mechanistic studies, CRISPR-Cas9-based genetic studies, cell biology and animal model-based translational studies, and proteomic analysis of ovarian cancer patient samples, to study ARID1A-regulated checkpoint axis in OCCC radioresistance and treatment. The rationale for the proposed project is that it will advance understanding of how deficiency of chromatin remodeling factor ARID1A, the most frequently mutated gene in OCCC, confers radioresistance, and will identify novel targeted therapeutic strategies and patient stratification biomarkers for OCCC. Our proposal is highly innovative because it focuses on a previously unexplored mechanism and will fill an important gap in understanding of ovarian cancer response to treatment. Our proposed studies will have a significant impact on functionalizing cancer genomic data to improve treatment outcomes of patients with ARID1A-deficient tumors or more broadly SWI/SNF-mutant cancers.

描述 卵巢透明细胞癌（OCCC）是第二种最常见的卵巢癌。不像其他 OCCC对标准的DNA损伤诱导治疗没有反应，包括 以铂为基础的化疗和放疗。卵巢癌患者的生存率一般很低。 由于缺乏有效的治疗，晚期OCCC患者的总生存率为 明显短于其他类型卵巢癌患者。我们的长期目标是 了解OCCC耐药的分子机制，并将这些发现转化为 有意义的临床应用。 最近的基因组研究表明，ARID 1A，染色质重塑复合物的一个组成部分， SWI/SNF是OCCC中最常见的突变基因。我们发现了一个新的泛素依赖的作用， ARID 1A对辐射诱导的DNA损伤的反应。本申请的目的是确定如何 ARID 1A缺陷通过泛素化调节导致异常的DNA损伤检查点， 我们可以通过靶向ARID 1A缺陷来改善OCCC的DNA损伤诱导治疗。 我们广泛的初步数据支持我们建议的中心假设：ARID 1A缺陷 通过失去ARID 1A以前未知的E3连接酶/泛素化促进适应性检查点反应 针对检查点蛋白CHK 2的活性，这创造了基于检查点的治疗机会 在ARID 1A突变型癌症中ATR-CHK 1检查点信号传导受损的背景下，我们将 采用多学科方法，包括基于生物化学的机制研究，基于CRISPR-Cas9的 遗传学研究、细胞生物学和基于动物模型的翻译研究，以及卵巢癌的蛋白质组学分析。 癌症患者样本，以研究ARID 1A调节的检查点轴在OCCC辐射抗性和治疗中的作用。 该项目的基本原理是，它将促进对染色质缺陷如何影响细胞的理解。 重塑因子ARID 1A是OCCC中最常见的突变基因，赋予辐射抗性， 确定OCCC的新靶向治疗策略和患者分层生物标志物。我们的建议是 高度创新，因为它侧重于以前未探索的机制，并将填补一个重要的空白， 了解卵巢癌对治疗的反应。我们提出的研究将产生重大影响， 功能化癌症基因组数据以改善ARID 1A缺陷肿瘤患者的治疗结果 或更广泛地说SWI/SNF突变型癌症。