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Cancer: Repurposing drugs as new treatments for breast cancer

PGR-P-811

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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 Paul Meakin
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. New approaches are therefore desperately needed.<br />

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

<p>Recent studies in glioblastoma and melanoma have identified a new class of drugs offering potential as cancer therapeutics. These drugs have been developed for treatment of Alzheimer&rsquo;s disease and inhibit the activity of the aspartic acid protease BACE1. However, high expression of BACE1 is linked to poor prognosis in TNBC and so BACE1 inhibitors are also promising candidates for treating TNBC.</p> <p>BACE1 functions to cleave membrane proteins leading to changes in function. This can have dramatic effects on a diverse range of signaling pathways and responses. Given the broad actions of BACE1, changes to the tumour, immune and endothelial cell secretome following BACE1 knockdown/inhibition using state-of-the-art mass spectrometry-based proteomics will be a primary aim of the project to provide focus. Following on from this, endpoint assays measuring effects of BACE1 on hallmarks of cancer (metabolic reprofiling, growth, migration, motility, invasion) and subsequent modulation of the efficacy of chemotherapy will be a particular focus.&nbsp;</p> <p>Previous reports suggest that BACE1 can modulate tumour cell growth (1). In support of this, our recent work suggests that BACE1 plays an important role in metabolic reprogramming (2), immune cell recruitment, and therefore tumour immunosurveillance. Additionally, BACE1 is critical for endothelial cell function (3) &ndash; and therefore implicated in vascularisation of tumours&nbsp;<em>in vivo</em>.&nbsp;</p> <p>This project will therefore fully characterize the role of BACE1 in breast:endothelial cell, and breast:immune cell crosstalk using BACE1 inhibitors and siRNA against BACE1 using 2D and 3D co-culture models in order to closely mimic tumour micro-environment. Key findings will also be validated using isolated cells and tissues from BACE1 knockout mice,&nbsp;<em>in vivo</em>models of cancer and patient derived cells and tissues.&nbsp;</p> <p>The outcomes from this project could have huge potential for improving TNBC treatment through &lsquo;drug-repurposing&rsquo;.</p> <p>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 2D and 3D TNBC coculture models; drug treatments; plasmid and siRNA transfection; mass spectrometry-based proteomics; 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> <p>References:</p> <ol> <li>Paris&nbsp;D, et al. Eur J Pharmacol.&nbsp;2005;514(1):1-15.&nbsp;doi: 10.1016/j.ejphar.2005.02.050.</li> <li value="2">Hamilton DL, et al. Diabetologia.&nbsp;2014;57(8):1684-92.&nbsp;doi: 10.1007/s00125-014-3269-x.</li> <li value="3">Meakin PJ, et al.&nbsp;<em>J Clin Invest.</em>&nbsp;2020;130(8):4104-4117.&nbsp;doi.org/10.1172/JCI122237.</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 the applicants 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>&nbsp;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>&nbsp;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> <p>&nbsp;</p>

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

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.

<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: &acirc;&euro;&cent; British Council IELTS - score of 7.0 overall, with no element less than 6.5 &acirc;&euro;&cent; 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 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: fmhpgradmissions@leeds.ac.uk</p>


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