Mechanisms of radioresistance and strategies for radiosensitization in OCCC

OCCC 的放射抵抗机制和放射增敏策略

基本信息

批准号：
9564069
负责人：
Guang Peng
金额：
$ 36.88万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
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/9564069
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

项目摘要

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。与其他不同对于多种类型的卵巢癌，OCCC 对标准 DNA 损伤诱导治疗没有反应，包括以铂类为基础的化疗和放疗。卵巢癌患者的生存期一般较差。由于缺乏有效的治疗，晚期 OCCC 患者的总生存期很短。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 ARID1A，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。我们发现了一种新的泛素化依赖性作用 ARID1A 响应辐射引起的 DNA 损伤。该应用程序的目的是确定如何 ARID1A 缺陷通过泛素化调节导致异常 DNA 损伤检查点以及是否我们可以通过针对 ARID1A 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提案的中心假设：ARID1A 缺陷通过失去 ARID1A 先前未知的 E3 连接酶/泛素化来促进适应性检查点反应针对检查点蛋白 CHK2 的活动，根据检查点创造治疗机会 ARID1A 突变癌症中 ATR-CHK1 检查点信号受损的抑制剂。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 的研究遗传学研究、细胞生物学和基于动物模型的转化研究以及卵巢蛋白质组分析癌症患者样本，研究 OCCC 放射抗性和治疗中 ARID1A 调节的检查点轴。拟议项目的基本原理是，它将加深对染色质缺陷如何影响的理解重塑因子 ARID1A 是 OCCC 中最常突变的基因，具有放射抗性，并且会确定 OCCC 的新型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，因为它专注于以前未探索过的机制，并将填补一个重要的空白了解卵巢癌对治疗的反应。我们提出的研究将对功能化癌症基因组数据以改善 ARID1A 缺陷肿瘤患者的治疗结果或更广泛的 SWI/SNF 突变癌症。