Identification and functional characterisation of BRIT1/MCPH1 synthetic lethal genes to treat breast and ovarian cancer

Project description

Women who have undergone surgery for breast and ovarian cancer often have additional chemotherapy to kill residual cancer cells and prevent recurrence. Unfortunately, 30-40% of these patients’ tumour cells are resistant to these treatments.

We have identified reduced expression of BRIT1/MCPH1, a DNA damage response gene in a third of ovarian and breast cancer patients. These reductions were associated with increasing tumour grade and poor survival1-2. Recently we have performed two complementary large-scale druggable genome siRNA screens to identify BRIT1/MCPH1 synthetic lethal (SL) genes. SL genes are when mutations in one gene alone has no effect on cell viability, however, mutation in both genes leads to cell death. Thus, targeting a SL gene in a cancer with BRIT1/MCPH1 mutations should selectively kill the cancer cells but not normal cells.

Analysis of cell viability data from the two siRNA screens, one with BRIT1/MCPH1 knockdown the other without has been performed identifying a number of interesting candidate genes (including other DNA repair genes) which preferentially kill BRIT1/MCPH1 deficient cells. The top SL genes will be selected based on functional relevance and the commercial availability of chemotherapeutic drugs and/or small molecule inhibitors to these targets. Four individual, deconvoluted siRNAs will be used to validate potential SL hits. Functional studies will be performed to investigate the mechanism causing SL in BRIT1/MCPH1 deficient cells.

Potential biomarkers much as BRIT1/MCPH1 will enable us to identify new chemotherapeutic approaches to treat cancer patients that are resistant to current treatments.

The student will be based in the Leeds Institute of Biomedical and Clinical Sciences (LIBACS), School of Medicine, University Of Leeds. This project will provide research training in a range of techniques including siRNA gene knockdown, cell culture, RNA extraction, pathway analysis, Real-time PCR, immunofluorescence, western blotting, live cell imaging, DNA repair assays and drug cytotoxicity assays.

References

1. Richardson J, Shaaban AM, Kamal M, Alisary R, Ellis I, Speirs V, Green A & Bell SM (2011) Microcephalin is a novel prognostic marker in breast cancer associated with BRCA1 inactivation. Breast Cancer Res Treat, 127(3):639-48.
2. Alsiary R, Brüning-Richardson A, Bond J, Morrison EE, Wilkinson N & Bell SM (2014) Deregulated microcephalin and ASPM expression in ovarian epithelial cancers. PLoS ONE 15;9(5):e97059.

Entry requirements

This project is available immediately to both Home/EU rate applicants and International applicants who are able to self-fund their studies. Students must be able to provide the appropriate level of fees based on their fee status plus laboratory consumables costs per year. This is in addition to the provision of personal living expenses.

You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject. 

Candidates whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study, the Faculty minimum requirements are

• British Council IELTS - score of 6.5 overall, with no element less than 6.0.
• TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

How to apply

Applications can be made at any time. Potential applicants should initially contact the lead supervisor Dr Sandra Bell at with enquiries about this research project.

To formally apply for this project applicants should complete a Faculty Scholarship Application form and send this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates to the Faculty Graduate School. 

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly by email.

If you have already applied for other scholarships using the Faculty Scholarship Application form you do not need to complete this form again. Instead you should email to inform us you would like to be considered for this scholarship project.