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.

抽象的 同源重组（HR）是DNA损伤的重要DNA修复机制 由Parpi和铂引起。人力资源途径与卵巢癌密切相关 发展和化学抗性。最近的临床研究表明，PARP抑制剂和 铂可有效治疗具有BRCA1或BRCA2突变的卵巢癌，以及其他 编码与人力资源有关的蛋白质的基因。相反，涉及人力资源的因素促进维修 由PARP抑制剂和铂引起的DNA病变，这增强了HR能力 有助于化学疗法抗性。因此，针对人力资源途径可能是强大的 克服对基于DNA损伤的治疗的抗药性的策略。 在这里，我们建议研究一种调节人力资源的新的ATM-Syk-CTIP途径。我们发现 酪氨酸激酶SYK在人力资源中起重要作用。 Syk在免疫调节中的功能是 然而，尚未显示出良好的DNA修复功能。我们发现Syk 磷酸化CTIP并调节HR中的CTIP功能。 SYK本身也被磷酸化 ATM依赖的方式，并招募到DNA损伤部位。有趣的是，Syk是 过表达复发性的卵巢癌； SYK的高表达与结果不佳有关 OCS。此外，OC细胞系中SYK的抑制使OC细胞对PARPI或 顺铂。综上所述，我们假设ATM-Syk-CTIP途径是新的 人力资源的调节机制。抑制SYK敏感性OC细胞对顺铂或Parpi的抑制 将SYK作为卵巢癌的新型潜在治疗靶标或生物标志物 治疗。为了检验这一假设，我们提出以下特定目的：1。 Syk对人力资源的调节； 2。通过DNA损伤信号传导研究SYK的调节； 3。 使用类器官和小鼠模型确定OC中SYK在化学反应中的抑制作用。 我们的研究将揭示SYK在DNA修复中的新功能和对化学疗法的反应。 此外，它将揭示OC治疗中新的治疗靶标和生物标志物。