Sensitizing Ovarian Cancer To PARP inhibitor and platinum treatment

卵巢癌对 PARP 抑制剂和铂类治疗敏感

• 批准号: 10305524
• 负责人: Zhenkun Lou
• 金额: $ 36.37万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10305524
• 关键词: Affect; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Cancer Model; Cancer Patient; Cancer cell line; Carboplatin; Cells; Chemoresistance; Cisplatin; Clinic; Clinical Research; DNA Damage; DNA Repair; DNA lesion; Development; Disease; Genes; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Modification; Mutate; Organoids; Outcome; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Platinum; Play; Protein Tyrosine Kinase; Proteins; Radiation; Recurrence; Regulation; Resistance; Role; SYK gene; Serous; Signal Transduction; Site; Testing; Translations; Woman; Xenograft procedure; base; cancer cell; cancer therapy; chemotherapy; design; high risk; homologous recombination; immunoregulation; in vivo; inhibitor/antagonist; mouse model; new therapeutic target; novel; overexpression; recruit; response; targeted biomarker; targeted treatment; therapeutic biomarker; therapeutic target

Abstract Homologous recombination (HR) is an important DNA repair mechanism for DNA damage caused by PARPi and platinum. The HR pathway is closely associated with ovarian cancer development and chemoresistance. Recent clinical studies showed that PARP inhibitors and platinum are effective in treating ovarian cancers with mutations of BRCA1 or BRCA2, and other genes encoding proteins involved in HR. Conversely, factors involved in HR promote the repair of DNA lesions caused by PARP inhibitors and platinum, and this enhanced HR capability contributes to chemotherapy resistance. Therefore, targeting HR pathway may be a powerful strategy to overcome resistance to DNA damage-based therapy. Here we propose to study a new ATM-SYK-CtIP pathway that regulates HR. We found the tyrosine kinase SYK plays an important role in HR. SYK’s function in immune regulation is well established, however, its function in DNA repair has not been shown. We found that SYK phosphorylates CtIP and regulates CtIP function in HR. SYK itself is also phosphorylated in an ATM dependent manner and get recruited to the sites of DNA damage. Interestingly, SYK is overexpressed in recurrent ovarian cancers; high expression of SYK is related to poor outcome of OCs. Furthermore, inhibition of SYK in OC cell lines renders OC cells sensitize to PARPi or cisplatin. Taken together, we hypothesize that the ATM-SYK-CtIP pathway is a new regulatory mechanism for HR. Inhibiting of SYK sensitizes OC cells to cisplatin or PARPi, suggesting SYK as the novel potential therapeutic targets or biomarkers for ovarian cancer therapy. To test this hypothesis, we propose the following Specific Aims: 1. Investigate the regulation of HR by SYK; 2. Investigate the regulation of SYK by the DNA damage signaling; 3. Determine the inhibition of SYK in chemo-response in OCs using organoid and mouse models. Our studies will reveal the novel function of SYK in DNA repair and response to chemotherapy. In addition, it will reveal the new therapeutic targets and biomarkers in OC therapy.

摘要 同源重组是DNA损伤的重要修复机制 是由PARPi和铂引起的HR通路与卵巢癌密切相关 发育和耐药性。最近的临床研究表明，PARP抑制剂和 铂可有效治疗BRCA 1或BRCA 2突变的卵巢癌， 相反，参与HR的因子促进修复， PARP抑制剂和铂引起的DNA损伤，这增强了HR能力 导致化疗耐药性。因此，靶向HR途径可能是一种强有力的 克服对基于DNA损伤的治疗的抗性的策略。 在这里，我们提出研究一个新的ATM-SYK-CtIP途径，调节HR。 酪氨酸激酶SYK在HR中起重要作用，SYK在免疫调节中的功能是 然而，它在DNA修复中的功能尚未得到证实。我们发现SYK 磷酸化CtIP并调节HR中的CtIP功能。 ATM依赖的方式，并得到招募的DNA损伤的网站。有趣的是，SYK是 在复发性卵巢癌中过表达; SYK的高表达与不良结局相关 的OC。此外，OC细胞系中SYK的抑制使得OC细胞对PARPi或PARPi敏感。 顺铂综上所述，我们假设ATM-SYK-CtIP通路是一个新的 抑制SYK使OC细胞对顺铂或PARPi敏感， 提示SYK是卵巢癌新的潜在治疗靶点或生物标志物 疗法为了验证这一假设，我们提出了以下具体目标：1。探讨 通过SYK调节HR; 2.探讨SYK通过DNA损伤信号通路对细胞凋亡的调控作用; 3. 使用类器官和小鼠模型确定SYK在OC中的化学反应中的抑制。 我们的研究将揭示SYK在DNA修复和化疗反应中的新功能。 此外，它将揭示OC治疗中新的治疗靶点和生物标志物。