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Cancer: Mechanisms of nutrient-metabolic regulation of cancer chemotherapy resistance

PGR-P-1011

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Key facts

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

In healthy tissues, nutrient metabolism and detoxification are connected at the cellular and transcriptional levels to prevent toxic accumulation of metabolic intermediates. In cancer, aberrant metabolism and altered nutrient bioavailability alters cellular detoxification pathways. Such pathways can confer resistance to an array of anti-cancer drugs, which reduces survivorship.<br />

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

<p>Triple negative breast cancer has higher relapse rates and lower survival than other types of breast cancer, incidence and outcome have been linked to dietary parameters. We have recently shown that TNBC disease is distinct from other BCa subtypes in how it responds to changes in cholesterol metabolism<span class="superscript_text">1</span>, and that suppression of cholesterol metabolism reduces tumour growth in a range of cancers and model organisms<span class="superscript_text">2</span>. Most recently we found that aberrant intra-tumoural cholesterol metabolism is associated with early death in TNBC patients because it induces resistance to some of the most commonly used chemotherapy drugs<span class="superscript_text">3</span>. Pilot work has now suggested that expression of many other functional biomarkers of chemoresistance could be influenced by nutrient-responsive transcriptional networks.&nbsp;</p> <p>This study aims to improve our understanding of chemoresistance-nutrition-metabolic gene networks to predict response to therapy, and determine whether modifying a patient&#39;s diet could improve oncological outcome in this high-risk patient group. This project will test if additional nutrient-metabolism networks regulate cellular chemoresistance mechanisms, and, when combined with measures of body composition and nutritional intake may predict chemoresponse in cancer patients. The project will initially explore top candidates from our nutrient-chemoresistance network analyses using a range in vitro and bioinformatic approaches. A clinical trial is planned to determine if nutritional and body composition metrics of TNBC patients can predict tumour responses to chemotherapy at the molecular and histological levels.</p> <h5>Tequniques used in this project</h5> <p>Training will be provided in all aspects so previous specialized experience is not required. The project will use a range of bioinformatic, cell and molecular biology techniques to achieve the aims outlined above. This includes training in 2D and 3D TNBC co-culture models; drug treatments; plasmid and siRNA transfection; metabolic profiling; cell fate assays; 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 strong background knowledge and specific expertise that is particularly relevant to developing a research career in cancer biology.</p> <h5>References</h5> <ol> <li>Hutchinson SA, Lianto P, Roberg-Larsen H, Battaglia S, Hughes TA,&nbsp;<strong>Thorne JL</strong>(<strong>2019</strong>).<em>ER-Negative Breast Cancer Is Highly Responsive to Cholesterol Metabolite Signalling</em>.&nbsp;<span class="underline_text">Nutrients</span>. 11. doi:10.3390/nu11112618.</li> <li>Cioccoloni G, Soteriou C, Websdale A, Wallis L, Zulyniak MA, and&nbsp;<strong>Thorne JL</strong>(<strong>2020</strong>).&nbsp;<em>Phytosterols and phytostanols and the hallmarks of cancer: a systematic review and meta-analysis of whole organism models.</em><span class="underline_text">Critical Reviews in Food Science and Nutrition.</span>doi: 10.1080/10408398.2020.1835820</li> <li value="3">Hutchinson SA, Websdale A, Cioccoloni G, R&oslash;berg-Larsen H, Lianto P, Kim B, Rose A, Soteriou C, Wastall LM, Williams BJ, Henn MA, Chen JJ, Ma L, Moore JB, Nelson E, Hughes TA and&nbsp;<strong>Thorne JL</strong>(<strong>2021</strong>).&nbsp;<em>Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer.</em><span class="underline_text">Oncogene</span>(In Press) and&nbsp;<span class="underline_text">BioRxiv</span>doi.org/10.1101/2020.08.04.235697.</li> </ol> <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&nbsp;<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&nbsp;<a href="https://medicinehealth.leeds.ac.uk/downloads/download/130/faculty_graduate_school_-_scholarship_reference_form">references</a>on your behalf, directly to&nbsp;<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 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; e:&nbsp;<a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a>,</p>


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