BRCAREV: Unravelling how reversion mutations in the BRCA1 and BRCA2 tumour suppressor genes occur

BRCAREV：揭示 BRCA1 和 BRCA2 肿瘤抑制基因的回复突变如何发生

• 批准号: EP/Y010361/1
• 负责人: Lorena Magraner Pardo
• 金额: $ 25.55万
• 依托单位: Institute of Cancer Research
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY010361%2F1
• 关键词: BRCAREV; Unravelling; how; reversion; mutations

A fundamental question in cancer research is what determines the success of treatment. Currently, up to 25% of breast cancer patients (40-70% of the poor-prognosis Triple Negative subtype) and about 5% of prostate cancer patients have BRCA1/2 deficiency and are suitable for treatment with PARP inhibitors (PARPi). However, over 40% of these patients do not respond to this treatment due to resistance mechanisms, which are not fully characterised. We propose to address this question by studying how tumour cells become resistant to PARPi. In the BRCAREV project, we will combine in silico and "wet-lab" experimental approaches to dissect this problem and use the information gained in this work to generate a predictor that estimates the likelihood that a person with a particular BRCA1 or BRCA2 mutation will or will not develop resistance to PARPi. Therefore, this work will: (i) benefits patients with BRCA1/BRCA2 mutant cancers; (ii) establish some of the fundamental rules that govern how cancer-associated mutations cause drug resistance; (iii) allow both the host group (a pioneer group researching the implication of BRCA mutations in cancer) and the applicant (a highly trained researcher on cancer genomics through computational structural approaches) to combine their knowledge and to generate new one of BRCA-mutated cancer therapeutics as part of an interdisciplinary project of mutual synergistic benefit, to the researchers and patients.

癌症研究中的一个基本问题是什么决定了治疗的成功。目前，高达25%的乳腺癌患者（40-70%的预后不良的三阴性亚型）和约5%的前列腺癌患者具有BRCA 1/2缺陷，并且适合用PARP抑制剂（PARPi）治疗。然而，超过40%的患者由于耐药机制而对这种治疗没有反应，这些耐药机制尚未完全表征。我们建议通过研究肿瘤细胞如何对PARPi产生耐药性来解决这个问题。在BRCAREV项目中，我们将联合收割机和“湿实验室”实验方法结合起来，剖析这个问题，并利用这项工作中获得的信息来生成一个预测因子，估计具有特定BRCA 1或BRCA 2突变的人是否会对PARPi产生耐药性。因此，这项工作将：（i）使BRCA 1/BRCA 2突变型癌症患者受益;（ii）建立一些基本规则，指导癌症相关突变如何导致耐药性;（三）允许主机组（一个研究BRCA突变在癌症中的意义的先驱小组）和申请人（通过计算结构方法对癌症基因组学进行高度培训的研究人员），以联合收割机结合他们的知识，并产生新的BRCA-突变的癌症治疗作为相互协同效益的跨学科项目的一部分，给研究人员和患者。