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: 10610944
• 负责人: Zhenkun Lou
• 金额: $ 35.64万
• 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/10610944
• 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; Mutate; Organoids; Outcome; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Platinum; Play; Poly(ADP-ribose) Polymerase Inhibitor; Post-Translational Protein Processing; Protein Tyrosine Kinase; Proteins; Radiation; Recurrence; Regulation; Resistance; Role; SYK gene; Serous; Signal Transduction; Site; Testing; Woman; Xenograft procedure; cancer cell; cancer therapy; chemotherapy; design; efficacy evaluation; high risk; homologous recombination; immunoregulation; in vivo; inhibitor; mouse model; new therapeutic target; novel; overexpression; recruit; response; 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(HR)是DNA损伤的重要修复机制 由PARPI和白金引起。HR通路与卵巢癌密切相关 发展和化疗耐药性。最近的临床研究表明，PARP抑制剂和 铂在治疗BRCA1或BRCA2等突变的卵巢癌方面有效 编码与HR有关的蛋白质的基因。反之，人力资源参与的因素会促进修复 PARP抑制剂和铂引起的DNA损伤，这增强了HR能力 会导致化疗耐药。因此，靶向HR通路可能是一种强有力的 克服对DNA损伤治疗的抵抗力的策略。 在这里，我们建议研究一种新的ATM-SYK-CtIP途径来调节HR。我们发现 酪氨酸激酶SYK在HR中起重要作用。SYK在免疫调节中的作用是 然而，众所周知，它在DNA修复中的作用还没有显示出来。我们发现SYK 磷酸化CtIP并调节HR中的CtIP功能。SYK本身也在一种 ATM依赖的方式，并被招募到DNA损伤的站点。有趣的是，SYK是 在复发性卵巢癌中过度表达；SYK高表达与预后不良相关 OCS的成员。此外，抑制OC细胞中的SYK使OC细胞对PARPI或PARPI敏感 顺铂。综上所述，我们假设ATM-SYK-CtIP通路是一条新的 人力资源的管理机制。抑制SYK使OC细胞对顺铂或PARPI增敏， 提示SYK可作为卵巢癌治疗的新靶点或生物标志物 心理治疗。为了验证这一假设，我们提出了以下具体目标：1.调查 SYK对HR的调节；2.研究DNA损伤信号对SYK的调节作用； 用有机物和小鼠模型确定SYK在OCS化学反应中的抑制作用。 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，它还将揭示OC治疗的新的治疗靶点和生物标志物。