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

基本信息

批准号：
9134662
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
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9134662
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 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

项目摘要

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（由申请人提供）：卵巢癌是美国最致命的妇科疾病，部分原因是缺乏对癌症如何对既定化疗（顺铂）和新兴抗癌疗法（PARPi）产生耐药性的了解。 ) 有效性在很大程度上依赖于内在的 DNA 损伤反应，最近的报告观察到，卵巢癌的初步实验表明，顺铂耐药的癌细胞对 PARP 抑制剂具有交叉耐药性。异常的 Wnt 信号传导通过调节非同源末端连接 (NHEJ) 途径导致对顺铂和 PARPi 的耐药性。本研究的总体目标是阐明 Wnt 依赖性 PARPi/顺铂在卵巢癌和乳腺癌中的耐药机制。开发一种使肿瘤细胞重新敏感的转化方法在 K99 指导阶段，我将努力明确异常 Wnt 信号传导的影响。（例如 Wnt5a 的缺失）和 NHEJ 在卵巢癌细胞中传递或维持化疗耐药性方面的作用，然后我将确定在耐药性疾病的背景下抑制经典 Wnt 和 NHEJ 途径的体内意义。卵巢癌模型（患者来源异种移植）以确定 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疗耐药性卵巢癌。这项工作将有助于阐明耐药过程，并可能对卵巢癌未来的治疗策略产生直接影响。