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  (MRC DTP CASE) Multiomic evaluation of differential drug response in metastatic breast cancers


   Faculty of Biology, Medicine and Health

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  Dr Sankari Nagarajan, Dr Hannah Harrison, Prof Robert Clarke, Dr Mudassar Iqbal  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

Breast cancers are the most common cancers in women. Estrogen Receptor (ER) plays a major role in breast cancer growth. To stop the cancer from growing further, clinically successful ER-targeting therapies like Fulvestrant, etc were developed. Yet, around 20% patients don’t respond to these drugs. Relapsed tumours from these patients spread to other organs (metastasis), which is deadly.

Astrazeneca’s recent clinical findings and another study1 found that Fulvestrant doesn’t work in patients, if they have metastasis to lung and or liver. Interestingly, our previous study along with another study2,3 identified the loss of a chromatin remodelling protein ARID1A to be a critical factor which can promote Fulvestrant resistance. Importantly, ARID1A loss leads to increased migration and metastasis of ER+ breast cancer cells to other organs.

We hypothesise that ARID1A loss leads to poor response of metastasized tumours to Fulvestrant in host organ-specific manner by associating with specific transcription factors and coactivators, modulated by stromal cells. To address this, the student will work with a multidisciplinary team to be trained in in vivo modelling, single cell transcriptomics and epigenomics, proteomics and machine learning, along with an industrial placement in Astrazeneca. They will utilise the Quasi vivo culture system, where breast cancer cells can be grown along with other cell lines of different organs where breast cancer spread (lung, liver, brain and lung fibroblasts) and stromal cells, in separate but interconnected chambers, resembling the human system. Using this model, the student will identify the comprehensive mechanisms of differential drug response, by growing the Fulvestrant-resistant cells with ARID1A perturbation homed to cells from different organs and stroma and by understanding the differences or patterns in:

·        the interactive changes in cell-specific gene expression,

·        DNA accessibility for transcription factors,

·        protein binding partners

This robust interdisciplinary project aims to hone the student in a diverse set of skills and make significant strides in addressing critical clinical knowledge gaps. The student will be trained to achieve better understanding of the gene regulation during cancer spread (disease mechanisms), further leading to predictive gene expression patterns of Fulvestrant response vs resistance, aiding in patient stratification. With the help of Astrazeneca, the student will also identify potential drug targets (developing interventions), to improve the response to Fulvestrant or to develop future treatments. Hence, this study will aid precision medicine by developing better treatment opportunities which promise better health care. 

Eligibility

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.

Before you Apply

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How to Apply

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC DTP website https://www.bmh.manchester.ac.uk/study/research/funding-fees/funded-programmes/mrc-dtp/

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team.

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/

Biological Sciences (4) Computer Science (8) Mathematics (25)

Funding Notes

This is a 4 year CASE studentship in partnership with AstraZeneca. This scheme is open to UK applicants only. Therefore, full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

1. He, M. et al. Metastatic breast cancer patients with lung or liver metastases should be distinguished before being treated with fulvestrant. Cancer Med. 8, 6212–6220 (2019).
2. Nagarajan, S. et al. ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response. Nat. Genet. 52, 187–197 (2020).
3. Xu, G. et al. ARID1A determines luminal identity and therapeutic response in estrogen-receptor-positive breast cancer. Nat. Genet. 52, 198–207 (2020).
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