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Cancer: Investigating Stress Hormone Modulators in Breast Cancer Treatment

PGR-P-460

Key facts

Type of research degree
4 year PhD
Application deadline
Ongoing deadline
Country eligibility
International (outside UK)
Funding
Non-funded
Supervisors
Dr Fiona Errington-Mais and Dr Laura Matthews
Additional supervisors
Prof Graham Cook
Schools
School of Medicine
Research groups/institutes
Leeds Institute of Medical Research at St James's
<h2 class="heading hide-accessible">Summary</h2>

Breast cancer (BC) is the most common cancer, with over 1 million new cases diagnosed worldwide each year. For some types of BC, hormonal treatments have been very effective but one particular BC subtype, triple negative breast cancer (TNBC), is highly aggressive and lacks a targeted therapy. Currently the only therapeutic options for TNBC is standard radiotherapy and chemotherapy. A new approach is to use oncolytic viruses (OV), which are emerging as effective therapies for a range of other cancers. OV preferentially kill cancer cells via two mechanisms &amp;ndash; by infecting and directly killing cancer cells, and by stimulating host anti-tumour immune responses, which in turn helps immune cells to detect and destroy cancer cells. However, multiple mechanisms exist within the tumour microenvironment which enable cancer cells to evade immune recognition or direct destruction by OV. One possible route is through the action of the anti-inflammatory stress hormone, glucocorticoids.

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

<p paraeid="{22787c9e-3832-48bd-968f-5d77fd09ff71}{87}" paraid="1330586000">Glucocorticoids (Gc) are steroid hormones important for normal physiology &ndash; with major actions on energy homeostasis, cell fate and immune function. The Gc Cortisol is released into the circulation with a daily rhythm which peaks in the morning, and is also elevated in response to stress. Cortisol has complex effects on cell fate and immunity &ndash; specifically the cells and pathways we know are important for OV action. To date, the impact of Cortisol on the efficacy of OV in TNBC has not been investigated. This project will systematically characterise the effect of the stress hormone Cortisol on OV function in TNBC. This will be achieved by examining the effect of Cortisol treatment on (i) OV driven killing of TNBC cells, (ii) OV driven inflammation and immune activation, and (iii) subsequent killing of TNBC by activated immune cells. Through this, the project will demonstrate which types of OV are most appropriate for treating TNBC, and also whether timing the treatment in line with Cortisol rhythms might further improve their efficacy. &nbsp;</p> <p paraeid="{22787c9e-3832-48bd-968f-5d77fd09ff71}{87}" paraid="1330586000">Training will be provided in all aspects, and so no specific previous experience is required. The project will use a range of bioinformatic, cell and molecular biology techniques to achieve the aims outlined above. This includes training in&nbsp;2D and 3D TNBC&nbsp;culture&nbsp;models; plasmid and siRNA transfection; viral&nbsp;propagation and&nbsp;infection; cell fate assays; ELISA; PCR; flow cytometry; immunoblotting and immunofluorescent microscopy. These broad skills provide a solid basis to pursue a career in most biology fields but the appointed student will develop background knowledge and specific expertise that is particularly relevant to developing a research career in the fields of cancer biology and/or immunology.&nbsp;</p> <p paraeid="{22787c9e-3832-48bd-968f-5d77fd09ff71}{103}" paraid="48969615">References:&nbsp;</p> <p paraeid="{22787c9e-3832-48bd-968f-5d77fd09ff71}{111}" paraid="1483464198">1. Matthews LC, Berry AA, Morgan DJ,&nbsp;Poolman&nbsp;TM, Bauer K, Kramer F, Spiller DG, Richardson RV, Chapman KE, Farrow SN, Norman MR, Williamson AJK,&nbsp;Whetton&nbsp;AD, Taylor SS,&nbsp;Tuckermann&nbsp;JP, White MRH, Ray DW. (2015) Glucocorticoid receptor regulates chromosome segregation and is associated with malignancy. PNAS. 112, 5479-5484.&nbsp;</p> <p paraeid="{22787c9e-3832-48bd-968f-5d77fd09ff71}{129}" paraid="1150781409">2. Gibbs J,&nbsp;Ince&nbsp;L, Matthews L, Mei J, Bell T, Yang N,&nbsp;Saer&nbsp;B, Begley N,&nbsp;Poolman&nbsp;T,&nbsp;Pariollaud&nbsp;M, Farrow S,&nbsp;DeMayo&nbsp;F,&nbsp;Hussell&nbsp;T, Worthen GS, Ray D, Loudon A. (2014) An epithelial&nbsp;circadian clock controls pulmonary inflammation and glucocorticoid action. Nature Medicine 20, 919-926.&nbsp;</p> <p paraeid="{22787c9e-3832-48bd-968f-5d77fd09ff71}{161}" paraid="562483995">3. Samson A, Scott KJ, Taggart D, West EJ, Wilson E, Nuovo GJ, Thomson S, Corns R, Mathew RK, Fuller MJ,&nbsp;Kottke&nbsp;TJ, Thompson JM,&nbsp;Ilett&nbsp;EJ, Cockle JV, Van&nbsp;Hille&nbsp;P, Sivakumar G, Polson ES, Turnbull SJ, Appleton ES,&nbsp;Migneco&nbsp;G, Rose AS, Coffey MC,&nbsp;Beirne&nbsp;DA, Collinson FJ, Ralph C,&nbsp;Anthoney&nbsp;DA, Twelves CJ, Furness AJ, Quezada SA,&nbsp;Wurdak&nbsp;H, Errington-Mais&nbsp;F,&nbsp;Pandha&nbsp;H, Harrington KJ, Selby PJ, Vile RG, Griffin SD, Stead LF, Short SC, Melcher AA. 2018. Intravenous delivery of oncolytic reovirus to brain&nbsp;tumor&nbsp;patients immunologically primes for subsequent checkpoint blockade. Science Translational Medicine 10, (422).&nbsp;</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 6.5 overall, with no element less than 6.0 &bull; 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.

<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&nbsp;Office&nbsp;</p> <p>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 research areas</h3>