Targeting Wnt signaling to overcome PARP inhibitor resistance in ovarian cancer

靶向 Wnt 信号传导克服卵巢癌中的 PARP 抑制剂耐药性

• 批准号: 8869244
• 负责人: Benjamin G Bitler
• 金额: $ 11.5万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8869244
• 关键词: Affect; Antineoplastic Agents; BRCA1 gene; BRCA2 gene; Biological Assay; Cancer Model; Cancer Patient; Cell Line; Cells; Cisplatin; Clinical; Clinical Management; DNA Damage; Data; Disease; Disease Resistance; Drug resistance; Effectiveness; Epithelial Cells; Epithelial ovarian cancer; Future; Gene Targeting; Goals; Health; Investigation; Ligands; Malignant Neoplasms; Malignant neoplasm of ovary; Mediator of activation protein; Mentors; Mutate; Nonhomologous DNA End Joining; Pathway interactions; Patients; Phase; Platinum; Play; Pre-Clinical Model; Prognostic Marker; Property; RNA Sequences; Relapse; Reporting; Research; Resistance; Resistance Process; Role; Signal Pathway; Signal Transduction; Slice; Testing; Therapeutic; Translating; United States; Work; XRCC5 gene; Xenograft procedure; anti-cancer therapeutic; base; beta catenin; cancer cell; cancer therapy; cell transformation; chemotherapy; clinical efficacy; drug sensitivity; in vivo; inhibitor/antagonist; loss of function; mutant; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; research study; response; restoration; sensor; transcriptome sequencing; translational approach; tumor; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): Ovarian cancer is the deadliest gynecological disease in the United States, which is due in part to the lack of understanding on how the cancer becomes resistant to chemotherapies. Established (cisplatin) and emerging anti-cancer therapeutics (PARPi) effectiveness rely heavily on intrinsic DNA damage response. Recent reports have observed that cisplatin-resistant cancer cells are cross-resistant to PARP inhibitors. Preliminary experiments in ovarian cancer indicate that aberrant Wnt signaling contributes to resistant to both cisplatin and PARPi by modulating the non-homologous end-joining (NHEJ) pathway. The overall goals of the proposed research is to elucidate the mechanism of Wnt-dependent PARPi/cisplatin resistant in ovarian cancer and to develop a translational approach to re-sensitize tumor cells. During the mentored K99 phase, I will work to clearly establish the impact aberrant Wnt signaling (e.g. loss off Wnt5a) and NHEJ has in conveying or maintaining chemoresistance in ovarian cancer cells. I will then determine the in vivo significance of inhibiting canonical Wnt and NHEJ pathways in the context of resistant disease. I will pursue the establishment of pre- clinical models of ovarian cancer (patient-derived xenograft) to determine if the modulation of Wnt signaling or NHEJ could be translated into the clinical setting to aid in the treatment of chemoresistant ovarian cancer. Excitingly, the proposed work will contribute to the elucidation of the resistant process and could have a direct impact on future therapeutic strategies for ovarian cancer.

 描述（由适用提供）：卵巢癌是美国最致命的妇科疾病，这部分是由于对癌症如何对化学疗法具有抗性的了解不足。建立（顺铂）和新兴抗癌治疗（PARPI）的有效性在很大程度上取决于内在的DNA损伤反应。最近的报道观察到，抗二铂抗癌细胞与PARP抑制剂交叉抗性。卵巢癌的初步实验表明，异常的Wnt信号传导通过调节非理论性终端加入（NHEJ）途径来有助于对顺铂和PARPI的抗性。拟议的研究的总体目标是阐明卵巢癌中Wnt依赖性PARPI/顺铂的机理，并开发一种转化方法来重新敏感性肿瘤细胞。在Mendored K99阶段，我将努力清楚地确定异常的Wnt信号传导（例如WNT5A的损失），并且NHEJ在输送或维持卵巢癌细胞的化学抗性方面具有。然后，我将在抗性疾病的背景下确定抑制规范Wnt和NHEJ途径的体内意义。我将建立卵巢癌的临床模型（患者衍生 异种移植物）是为了确定Wnt信号传导或NHEJ的调节是否可以转化为临床环境，以帮助治疗化学耐药性卵巢癌。令人兴奋的是，提议 工作将有助于阐明抵抗过程，并可能对卵巢癌的未来治疗策略产生直接影响。