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.

抽象的 同源重组（HR）是DNA损伤的重要DNA修复机制 由PARPi和铂引起的HR通路与卵巢癌密切相关。 最近的临床研究表明 PARP 抑制剂和 铂可有效治疗携带 BRCA1 或 BRCA2 突变的卵巢癌以及其他癌症 编码参与 HR 的蛋白质的基因脱机，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 因此，靶向 HR 通路可能是一种有效的方法。 克服对基于 DNA 损伤的治疗的耐药性的策略。 在这里，我们建议研究一种新的调节 HR 的 ATM-SYK-CtIP 途径。 酪氨酸激酶SYK在HR中发挥着重要的免疫调节作用。 然而，我们发现 SYK 在 DNA 修复中的功能尚未得到证实。 SYK 本身也被磷酸化 SYK 依赖 ATM 方式并被招募到 DNA 损伤位点。 SYK 在复发性卵巢癌中过度表达，与不良预后相关； 此外，抑制 OC 细胞系中的 SYK 会使 OC 细胞对 PARPi 或 敏感。 综上所述，我们勇敢地说 ATM-SYK-CtIP 途径是一条新途径。 HR 的抑制机制使 OC 细胞对顺铂或 PARPi 敏感， 建议 SYK 作为卵巢癌新的潜在治疗靶点或生物标志物 为了检验这一假设，我们提出以下具体目标： 1. 调查 SYK 对 HR 的调节； 2. 研究 SYK 对 DNA 损伤信号的调节； 使用类器官和小鼠模型确定 SYK 对 OC 化学反应的抑制作用。 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，还将揭示 OC 治疗的新治疗靶点和生物标志物。

项目成果

Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization.

异常的 ATM 信号传导和同源定向 DNA 修复是 p53 突变 GBM 对 AZD1390 介导的放射增敏的脆弱性。

• 发表时间: 2024-02-14
• 影响因子: 17.1
• 作者: Chen, Jiajia;Laverty, Daniel J;Talele, Surabhi;Bale, Ashwin;Carlson, Brett L;Porath, Kendra A;Bakken, Katrina K;Burgenske, Danielle M;Decker, Paul A;Vaubel, Rachael A;Eckel;Bhargava, Rohit;Lou, Zhenkun;Hamerlik, Petra;Harl
• 通讯作者: Harl