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Investigating new epigenetic regulators of targeted cancer therapy


Project Description

Deficiencies in the cellular response to DNA damage are intimately linked with tumour development, but also provide an opportunity to selectively eliminate tumour cells using targeted therapy. The first clinically-approved drugs exploiting defects in DNA repair were poly(ADP-ribose) polymerase inhibitors (PARPi). PARPi offer a powerful clinical option to treat certain kinds of hereditary breast and ovarian cancer caused by mutations in DNA repair factors such as BRCA1, and they are also being trialled for the treatment of other tumours including mesothelioma. However, significant drug resistance has been observed in patients and in pre-clinical models. Understanding this resistance and how it arises is crucial in order to use PARPi effectively.

Our studies have discovered a novel mechanism by which cancer cells can become resistant to PARP inhibitors: loss of an epigenetic modifying enzyme. To shed further light on these findings, this studentship will examine three questions:
1) Investigate the mechanisms behind this resistance: we predict that epigenetic changes govern how cells respond to PARPi. This objective aims to investigate this using a combination of RNA-seq, proteomics, and molecular and cellular biology techniques.
2) Study how we can target these resistant cells using other chemotherapies: combined loss of BRCA1 and the epigenetic modifier might render cells susceptible to other DNA-damaging compounds. To assess this, we will examine cell survival and genome integrity in vitro and in vivo.
3) Examine the clinical relevance in samples from mesothelioma patients treated with PARP inhibitors: PARPi are also in clinical trials for the treatment of mesothelioma, especially those tumours with mutations in other DNA damage response factors. This objective will use patient-derived material from individuals treated with PARPi to determine whether our findings affect PARPi sensitivity in the clinic.

This project will provide a greater understanding of the molecular mechanisms underlying PARPi resistance, with wide-ranging implications for clinical treatment of a variety of cancers.

Person Specification
Applicants should have a strong background in cellular and molecular biology, and ideally a background in DNA damage, epigenetics or cancer biology. Experience of a research lab environment is desirable, along with expertise in one or more of the following laboratory techniques: mammalian tissue culture; immunofluorescence; Western blotting or molecular cloning. They should have a commitment to research in the field of genome stability and epigenetics, and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant biological subject.

Funding Notes

Please check the MRC website for full eligibility criteria View Website

References

Bryant et al. 2005 Nature; 434(7035):913-7.
Ismail et al. 2014 Cancer Res; 74(16): 4282–94.
Gogola et al. 2018 Annu. Rev. Cancer Biol; 3:235–54
ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT03207347.

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