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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