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

PGR-P-392

Key facts

Type of research degree
4 year PhD
Application deadline
Ongoing deadline
Country eligibility
International (outside UK)
Funding
Non-funded
Supervisors
Dr Sandra Bell
Schools
School of Medicine
Research groups/institutes
Leeds Institute of Medical Research at St James's
<h2 class="heading hide-accessible">Summary</h2>

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&rsquo; tumour cells are resistant to these treatments.

<h2 class="heading hide-accessible">Full description</h2>

<p>We have identified reduced expression of BRIT1/MCPH1, a DNA damage response gene in a third of breast cancer patients. These reductions were associated with increasing tumour grade and poor survival1. 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.&nbsp;</p> <p>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.&nbsp;<br /> Potential biomarkers much as BRIT1/MCPH1 will enable us to identify new chemotherapeutic approaches to treat breast cancer patients that are resistant to current treatments.&nbsp;<br /> &nbsp;</p> <p><strong>Tequniques used in this project</strong></p> <p>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 cytoxicity assays.&nbsp;</p> <p><strong>References</strong></p> <p>1. Richardson J, Shaaban AM, Kamal M, Alisary R, Ellis I, Speirs V, Green A &amp; Bell SM (2011) Microcephalin is a novel prognostic marker in breast cancer associated with BRCA1 inactivation. Breast Cancer Res Treat, 127(3):639-48.&nbsp;</p> <p>2.Alsiary R, Br&uuml;ning-Richardson A, Bond J, Morrison EE, Wilkinson N &amp;&nbsp;Bell SM(2014) Deregulated microcephalin and ASPM expression in ovarian epithelial cancers. PLoS ONE15;9(5):e97059.</p> <p>This project is part of the&nbsp;<a href="https://medicinehealth.leeds.ac.uk/leeds-institute-research-st-james/doc/international-phd-academy-medical-research">International PhD Academy: Medical Research</a></p> <p><strong>In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.</strong></p>

<h2 class="heading">How to apply</h2>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. To apply for this project applicants should complete an <a href="http://www.leeds.ac.uk/info/130206/applying/91/applying_for_research_degrees">online application form</a> and submit this&nbsp;alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates. Please make it clear in the research information section that you are applying for the International PhD Academy: Medical Research, as well as the title of the project you wish to be considered for.</p> <p>We also require 2 academic references to support your application. Please ask your referees to send these <a href="https://medicinehealth.leeds.ac.uk/downloads/download/130/faculty_graduate_school_-_scholarship_reference_form">references</a> on your behalf, directly to <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p>

<h2 class="heading heading--sm">Entry requirements</h2>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

<h2 class="heading heading--sm">English language requirements</h2>

Applicants 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 of Medicine and Health minimum requirements in IELTS and TOEFL tests for PhD, MSc, MPhil, MD are: &bull; British Council IELTS - score of 7.0 overall, with no element less than 6.5 &bull; TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.

<h2 class="heading">Contact details</h2>

<p>Informal enquires about regarding the bespoke taught first year of the PhD programme and research projects can be made by contacting LIMRPhD@leeds.ac.uk</p> <p>Enquiries regarding the application process should be directed to the Faculty of Medicine and Health Graduate School Office e: <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a>, t: +44 (0)113 343 8221.</p>


<h3 class="heading heading--sm">Linked funding opportunities</h3>
<h3 class="heading heading--sm">Linked research areas</h3>