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.
Chromatin remodeling factor ARID1A has been identified as the most frequently mutated gene in ovarian clear-cell carcinoma (OCCC), which exhibits intrinsic resistance to DNA damage- inducing treatment, including radiotherapy. In this application, we aim to investigate the role of ARID1A in cellular responses to radiation-induced DNA damage. By functionalizing genomic sequencing data, the knowledge gained in this study will improve understanding of key mechanisms in OCCC radioresistance and, more importantly, identify clinically applicable strategies for radiosensitization of OCCC.
| Peng, Guang; Mills, Gordon B (2018) Surviving Ovarian Cancer: An Affair between Defective DNA Repair and RB1. Clin Cancer Res 24:508-510 |
| Shen, Jianfeng; Ju, Zhenlin; Zhao, Wei et al. (2018) ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med 24:556-562 |
| Hsieh, Hui-Ju; Zhang, Wei; Lin, Shu-Hong et al. (2018) Systems biology approach reveals a link between mTORC1 and G2/M DNA damage checkpoint recovery. Nat Commun 9:3982 |
| Shen, Jianfeng; Zhao, Wei; Ju, Zhenlin et al. (2018) PARPi triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness. Cancer Res : |
| Peng, Yang; Scott, Paul; Tao, Ruikang et al. (2017) Dissect the Dynamic Molecular Circuits of Cell Cycle Control through Network Evolution Model. Biomed Res Int 2017:2954351 |
