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

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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