부산대학교 도서관

High Grade Serous Ovarian Cancer (HGSOC) is one of the most aggressive gynaecological malignancies in women. Anti-VEGFA therapy in combination with chemotherapy has shown promise for the treatment of HGSOC. However, as not all women benefit and side effects can be severe, predictive biomarkers are urgently needed to improve treatment outcome. As high plasma levels of the VEGFA isoform VEGFA121 had shown promise as a prognostic and predictive biomarker in breast, gastrointestinal and pancreatic cancer, this project aimed to investigate the potential of VEGFA isoform measurement as a biomarker in HGSOC. Analysis of RNAseq data from The Cancer Genome Atlas Ovarian (TCGA OV) dataset was used to investigate associations between VEGFA mRNA isoform expression and clinical outcome. Different methods were explored for the development of novel ovarian cancer cell lines expressing increased VEGFA121. These were characterised in vitro and then in in vivo pre-clinical models of advanced disease. Analysis of RNAseq data showed different patterns of VEGFA mRNA isoform expression exists between HGSOC patient's tumours. Segregation based on VEGFA165 expression had the strongest correlation with prognosis, with low levels of VEGFA165 associated with significantly decreased overall survival (HR 2.0, 95% CI 1.24-3.23, p-value 0.005). HGSOC tumours with low VEGFA165 also had increased expression of VEGFA121 mRNA. The VEGFA165-high group, with low expression of VEGFA121, had increased expression of genes associated with improved response to bevacizumab, hypoxia (e.g. MTOR, PDK1, ANGPLT4 and CA9) and angiogenesis (e.g. FLT1, KDR, DLL4 and NOTCH4) (FDR < 0.05). In vitro, ID8 mouse ovarian cancer cells overexpressing VEGFA120 (ID8 120) had decreased proliferation and migration. Mice injected with ID8 120 cells took longer to reach clinical end points and had a reduced response to anti-VEGFA antibodies compared to mice injected with ID8 cells. However, neither was statistically significant. In conclusion, although measurement of VEGFA mRNA isoform expression may have use as a prognostic and predictive biomarker after further characterisation, further efforts are needed to develop pre-clinical models to improve understanding of underlying mechanisms.