Targeting Fanconi Anemia pathway to overcome platinum drug resistance in ovarian cancer

靶向范可尼贫血途径克服卵巢癌铂类药物耐药性

• 批准号: 10117536
• 负责人: Wenge Zhu
• 金额: $ 43.59万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10117536
• 关键词: Biological Assay; Cancer Biology; Cancer Etiology; Cancer Patient; Cell Survival; Cessation of life; Clinical; Clinical Oncology; DNA Interstrand Crosslinking; DNA biosynthesis; DNA replication fork; Data; Development; Disease; Disease remission; Drug resistance; Fanconi Anemia pathway; Fanconi' s Anemia; G1 Phase; Genetic; High Mobility Group Proteins; In Vitro; Laboratory Finding; Lead; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of ovary; Mediating; Modeling; Molecular; Oncogenes; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phosphorylation; Platinum; Proteins; Refractory; Regulation; Reporting; Resistance; Role; Signal Transduction; Site; Testing; Therapeutic; Time; United States; Woman; Yeasts; base; cancer cell; cancer therapy; chemotherapy; crosslink; drug discovery; experimental study; high throughput screening; in vivo; inhibitor/antagonist; innovation; insight; multidisciplinary; novel; novel strategies; novel therapeutic intervention; novel therapeutics; patient population; recruit; repaired; standard care; therapy resistant; tool; treatment strategy; tumor

Project Summary Ovarian cancer (OC) is the fifth leading cause of cancer-related death among women and the deadliest gynecological cancer in the United States. The current standard treatment for ovarian cancer consists of surgery followed by platinum drug-based chemotherapy. Platinum drugs could induce DNA interstrand crosslink (ICL), which results in replication fork stalling and thus decrease cell viability. Although most of patients initially respond to platinun drug-based chemotherapy and achieve remission, up to 80% of patients become refractory to platinum drugs over time and ultimately succumb to the disease due to the resistance to platinum-based therapy. Thus, it is urgent to develop novel approaches to overcome platinum drug resistance of ovarian cancer (PROC). Fanconi anemia (FA) pathway is critical to repair ICLs and elevated activity of FA signaling is one of major mechanisms leading to platinum-resistance in ovarian cancer. The role of FA pathway in repair of ICL has been well studied last decade, however, how the regulatory switch from a stalled replication fork caused by platinum drugs to initiation of FA signaling and how FA is activated in PROC cells are poorly understood. To elucidate the mechanism regulating initiation of FA signaling, we have conducted the significant amount of preliminary studies to demonstrate that And-1 is critical for activation of FA signaling and FA- mediated platinum drug resistance in ovarian cancer. The major objective of this proposal is to determine the mechanism of how And-1-FANCM axis regulates FA signaling and platinum resistance in PROC. Here, we propose three specific aims. Aim 1: Determine how And-1 promotes the switch from stalled replication forks to initiation of FA signaling at ICLs. Aim 2: Determine the role of And-1 in the regulation of platinum drug resistance in PROC cells. Aim 3: Evaluate the effects of And-1 inhibition on platinum drug resistance using orthotopic PROC PDX and syngeneic models. The completion of proposed studies will not only elucidate a novel mechanism regulating platinum resistance in PROC, but also provide an innovative therapeutic strategy as well as a new potential drug for treatment of PROC patients.

项目总结