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: 9763331
• 负责人: Guang Peng
• 金额: $ 35.48万
• 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/9763331
• 关键词: 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; Radiation-Sensitizing Agents; Radioresistance; 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 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)是第二常见的卵巢癌类型。不同于其他 对于各种类型的卵巢癌，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。一般来说，卵巢癌患者的存活率很低。 由于治疗缺乏疗效，晚期OCCC患者的总体生存时间为 明显短于其他类型卵巢癌患者。我们的长期目标是 了解OCCC治疗耐药的分子机制，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，染色质重塑复合体的一种成分ARID1A Swi/Snf是OCCC中最常见的突变基因。我们发现了一种新的泛素化依赖的角色 ARID1A对辐射诱导的DNA损伤的反应。此应用程序的目标是确定如何 ARID1A缺乏通过泛素化调节导致DNA损伤检查点的异常，以及 我们可以通过针对ARID1A缺乏症来改善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：ARID1A缺陷 通过ARID1A先前未知的E3-连接酶/泛素化缺失促进适应性检查点反应 针对检查点蛋白Chk2的活性，它基于检查点创造治疗机会 ARID1A突变癌症中ATR-CHK1检查点信号受损背景下的抑制剂。我们会 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 卵巢的遗传学研究、细胞生物学和动物模型的翻译研究以及蛋白质组学分析 以癌症患者为样本，研究ARID1A调节的检查点轴在OCCC辐射抵抗和治疗中的作用。 拟议项目的基本原理是，它将增进对染色质缺乏的理解 重塑因子ARID1A，OCCC中最常见的突变基因，赋予辐射抗性，并将 为OCCC确定新的靶向治疗策略和患者分层生物标记物。我们的建议是 极具创新性，因为它专注于以前未曾探索过的机制，并将填补 了解卵巢癌的治疗反应。我们建议的研究将对以下方面产生重大影响 将癌症基因组数据功能化以改善ARID1A缺陷肿瘤患者的治疗结果 或者更广泛地说，SWI/SNF突变的癌症。