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Targeting the Achilles’ heel – dissecting drug resistance in ovarian cancer


Project Description

Ovarian cancer, the most common cause of gynaecological cancer death, is frequently diagnosed when the disease is already advanced, when surgery is not always possible. Response to chemotherapy is therefore a critical determinant of outcome in the majority of ovarian cancer patients, many of whom initially respond well to combination treatment with the most commonly prescribed drugs carboplatin and paclitaxel. Unfortunately, however, ovarian cancers frequently adapt to avoid being killed by toxic chemotherapy drugs, modifying their behaviour to create drug resistant cancers which no longer respond to treatment. To understand the underlying molecular mechanisms, we have created novel drug-sensitive and drug-resistant cell line models which mimic typical clinical treatments, and have used RNASeq analysis and Reverse Phase Protein Array (RPPA) profiling to identify genes and proteins, the expression of which is changed as cells become drug resistant. We have shown that the expression of specific proteins, for example the phosphorylated forms of the serine/threonine protein kinase AKT (protein kinase B), is higher in drug resistant cells, thus identifying candidate proteins which can be targeted with highly specific small molecule inhibitors – using the clinical trial drug MK-2206 to inhibit pAKT, for example, allowed us to re-sensitise drug-resistant cells to both carboplatin and paclitaxel chemotherapy. Further analysis of this unique dataset has identified multiple differences in receptor tyrosine kinase signaling pathways in drug-resistant cells, characteristic of phenotypic changes induced by an epithelial-mesenchymal transition, resulting in functionally-important differences in cell morphology, proliferation and metastatic potential. The aim of this translational PhD project will therefore be to use a wide variety of complementary experimental approaches (including qRT-PCR analysis, Western blotting, siRNA-mediated gene knockdowns, chemosensitivity and phenotypic assays) to investigate the role of our prioritised candidate genes in drug resistance, with a particular focus on developing novel combination chemotherapy approaches and quantitative drug resistance biomarkers. Ourin vitro experiments described above will be complemented, in collaboration with our wider clinical research team, by analysis of matched primary ascites-derived cell lines created from initially drug-sensitive and subsequently drug-resistant ovarian cancer patients collected as they progress through treatment in the Dundee Ovarian Cancer Study (DOCS). Availability of DOCS study samples provides a unique opportunity both to further validate prioritised targets in well-characterised clinical samples, and to use the unbiased profiling approaches described above for additional target discovery.



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To apply please send a cover letter, curriculum vitae and two references to:

Funding Notes

Please note this is a self-funded PhD project

References

Sawers L, Ferguson MJ, Ihrig BR, Young HC, Chakravarty P, Wolf CR, Smith G (2014) Glutathione S-transferase P1 (GSTP1) directly influences platinum drug chemosensitivity in ovarian tumour cell lines. British Journal of Cancer 111(6): 1150-8
Smith G, Ng MT, Shepherd L, Herrington CS, Gourley C, Ferguson MJ, Wolf CR (2012) Individuality in FGF1 expression significantly influences platinum resistance and progression-free survival in ovarian cancer. British Journal of Cancer 107(8): 1327-36
Vaidyanathan A, Sawers L, Gannon AL, Chakravarty P, Scott AL, Bray SE, Ferguson MJ, Smith G (2016) ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells. British Journal of Cancer 115(4): 431-41

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