Sir Peter MacCallum Department of Oncology - Theses

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    Cyclin E1 as a therapeutic target in high grade serous ovarian cancer
    Au-Yeung, George ( 2017)
    The central theme of this thesis is developing therapeutic strategies to selectively target CCNE1 amplified high grade serous ovarian cancer (HGSC). Patients with CCNE1 amplified HGSC represent a key unmet clinical need given that they are associated with primary treatment resistance and poor clinical outcome. Novel therapeutic strategies are urgently required in order to provide these patients with additional treatment options. Using short interfering RNA and short hairpin RNA, I demonstrated selective sensitivity of CCNE1 amplified HGSC to CDK2 gene suppression. However, I did not demonstrate similar amplicon dependent sensitivity to dinaciclib, a potent small molecule inhibitor of multiple CDKs. In order to identify drug combinations that would synergise with dinaciclib, I performed a high throughput compound screen in CCNE1 amplified HGSC cell lines. I identified a combination of dinaciclib and MK-2206, an AKT inhibitor, that was selectively synergistic in in vitro and in vivo models of CCNE1 amplified HGSC. CCNE1 and AKT2 were noted to be co-amplified in primary HGSC samples, and a number of genes in the AKT pathway were found to be required in CCNE1 amplified HGSC cell lines. Furthermore, over-expression of cyclin E1 and AKT isoforms resulted in uncontrolled growth characteristics in TP53-mutant fallopian tube secretory cells, the proposed cell of origin for HGSC. Taken together, these findings suggest that co-operative interaction between CCNE1 and the AKT pathway in HGSC may be exploited therapeutically. I also explored the potential mechanisms of resistance to CDK inhibitors by generating cell lines resistant to dinaciclib. Dinaciclib in combination with multiple BH3-mimetic compounds was noted to be synergistic in CDK-inhibitor resistant cell lines. Upregulation of multiple anti-apoptotic genes was observed in resistant cell lines compared to parental sensitive cell lines, suggesting that this is a potential mechanism of resistance to CDK inhibitors. Targeting homologous recombination (HR) may also be a therapeutic option in CCNE1 amplified HGSC. Proteasome inhibitors such as bortezomib have been shown to be indirect inhibitors of HR, and I showed that CCNE1 amplified cell lines were highly sensitive to bortezomib and MLN9708, a second generation proteasome inhibitor. Potential synergistic combinations with bortezomib were identified in a high throughput compound screen, including a number of HDAC inhibitors, suggesting a possible class effect.