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Tackling drug resistance – a role for precision medicine in ovarian cancer


School of Medicine

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Dr G Smith , Dr M Ferguson No more applications being accepted Funded PhD Project (Students Worldwide)
Dundee United Kingdom Cancer Biology

About the Project

Division: Cellular Medicine

Start Date: 20/09/21

Ovarian cancer, the most deadly gynaecological malignancy, frequently presents late, when chemotherapy is the most appropriate treatment (1). Response to first-line chemotherapy is variable, however, and a significant outcome predictor. Although many patients respond well, chemotherapy-induced “adaptive” drug resistance is common, while some 30% of patients are inherently drug resistant (2). Development of mechanism-based, biomarker-guided precision medicine approaches for chemotherapy prescribing in ovarian cancer would help clinicians to optimise drug selection and limit exposure to ineffective toxic drugs.

We have designed a longitudinal clinical study, the Dundee Ovarian Cancer Study (DOCS), creating matched series of serial blood samples and primary ascites-derived cell lines from drug-sensitive and drug-resistant patients. The DOCS study provides a unique opportunity to identify novel clinically relevant resistance mechanisms, and to develop quantitative biomarker assays.

To date (3-5), we have focussed on adaptive drug resistance mechanisms, using unbiased whole genome RNASeq and RPPA analysis to compare mRNA expression in drug-sensitive and drug-resistant patients. Bioinformatics analysis highlights marked inter-patient variation in gene expression, and has excitingly allowed us to identify common candidate drug resistance signatures consisent with expansion of a sub-population of inherently resistant cancer stem cells. The focus of this translational PhD project will focus on inherent drug resistance, correlating laboratory analysis (bioinformatics analysis of RNASeq and RPPA datasets, qRT-PCR analysis, Western blotting, immunohistochemical analysis, quantitative chemosensitivity, cell proliferation, invasion, migration and apoptosis assays following over-expression and siRNA-mediated transient gene knockdown) with detailed clinical histories from patients who responded well or were inherently resistant to first-line chemotherapy. 

Apply

Applicants to complete the Application form and email to [Email Address Removed] along with a CV and 2 academic references by Monday 22nd March 2021.

Eligibility Requirements

First class honours degree, and/or a Masters degree in a relevant discipline. (Non-clinical applicants)

MBChB (clinical applicants)

English language requirements

IELTS minimum overall score of 6.5

Reading 5.5, Listening 5.5, Speaking 5.5 Writing 6.0


Funding Notes

Funded by the Ninewells Cancer Campaign
RCUK stipend rate for 4 years (non-clinical applicants)
or
University of Dundee Clinical Research Fellow scale for 3 years (clinical applicants)

References

1. Scottish Intercollegiate Guidelines Network (SIGN). Management of epithelial ovarian cancer. Edinburgh: SIGN; 2013. (SIGN publication no. 135). http://www.sign.ac.uk
2. Vaughan S, et al. (2011) Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 211(10):719-25.
3. Smith G, et al. (2012) Individuality in FGF1 expression significantly influences platinum resistance and progression-free survival in ovarian cancer. British Journal of Cancer 107(8): 1327-1336
4. Sawers L, et al. (2014) Glutathione S-transferase P1 (GSTP1) directly influences platinum drug chemosensitivity in ovarian tumour cell lines. British Journal of Cancer 111(6): 1150-1158.
5. Vaidyanathan A, et al. (2016) ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel and olaparib-resistant ovarian cancer cells. British Journal of Cancer 115: 431-441


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