Genomic and functional analysis of new potential combination therapies targeting DNA damage response in high grade serous ovarian carcinoma

HGSC的特征在于由DNA损伤修复（DDR）途径中的突变过程驱动的染色体不稳定性（CIN）。主要的临床需求是开发新的组合DDR疗法以增加临床有效性并限制耐药性的演变。Varsity Pharmaceuticals正在通过重新利用临床上用于非癌症适应症的疗法来开发针对几种DDR途径（POLQi，TrxRi和ATRi）的药物。Brenton实验室已经开发出拷贝数签名来表征HGSC中CIN的原因，该签名使用全基因组测序数据区分复杂的突变过程，并通过整合不同的基因组特征集提供预测性治疗信息。我们正在开发使用DNAseq的单细胞分析的活性突变过程的详细表征，RNAseq和CyTOF.AIM 1在已建立的基于细胞的HGSOC模型中对DDR靶向化合物进行表型分析，以确定活性和作用机制AIM 2开发使用类器官和小鼠模型的集中的体外和体内治疗研究，以建立预治疗模型。转化为临床试验的临床证据实验方法将使用高度表征的HGSOC模型，包括癌症类器官和原发性患者样本。主要技术包括全基因组测序分析、RNA分析和DDR生物标志物的多参数细胞术。Varsity Pharmaceuticals是一家总部位于剑桥的肿瘤学公司，致力于开发药物以解决癌症治疗的耐药性。该项目提供了一个3个月的安排在Varsity工作的早期阶段项目开发团队，以促进学术研究的临床开发的翻译。该项目具有直接的翻译相关性，对患有HGSC的女性的精准医学产生了重大影响。此外，从现有药物中确定新活性并重新利用它们的策略将确保快速过渡到癌症患者的治疗研究

HGSC is characterized by chromosomal instability (CIN) driven by mutational processes in DNA damage repair (DDR) pathways. The major clinical need is to develop new combination DDR therapies to increase clinical effectiveness and limit the evolution of resistance. Varsity Pharmaceuticals is developing medicines targeting several DDR pathways (POLQi, TrxRi, and ATRi) by repurposing therapies that have been used clinically for non-cancer indications.The Brenton lab have developed copy number signatures to characterize the causes of CIN in HGSC that distinguish complex mutational processes using whole genome sequencing data and provide predictive therapeutic information by integrating diverse sets of genomic features. We are developing detailed characterization of active mutational processes using single cell profiling with DNAseq, RNAseq and CyTOF.AIM 1Phenotyping of DDR targeting compounds in established cell-based HGSOC models to establish activity and mechanism of actionAIM 2Development of focused in vitro and in vivo therapeutic studies using organoid and mouse models to establish pre-clinical evidence for translation to clinical trialsThe experimental approaches will use highly characterized HGSOC models including cancer organoids and primary patient samples. The main techniques include whole genome sequencing analysis, RNA profiling and multi-parameter cytometry for DDR biomarkers.Varsity Pharmaceuticals is a Cambridge-based oncology company developing drugs to tackle resistance to cancer therapies. The project provides a 3 month placement at Varsity to work within the early-phase project development team to contribute to the translation of academic research to clinical development. The project has direct translational relevance with major impacts on precision medicine for women with HGSC. In addition, the strategy of identifying new activities from existing medicines and repurposing them will ensure rapid transition into therapeutic studies in cancer patients