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(MCRC Non-Clinical) Defining the Bcl-2 family interactome to optimise breast cancer cell response to chemotherapy

Project Description

Project summary:
More than 80% of breast cancer (BC) patients can be treated with targeted drugs like tamoxifen or trastuzumab, which have significantly reduced mortality rates over the past 20 years. However, therapy resistant or triple negative BC cannot be treated with targeted drugs, and patients with these types of BC are given on chemotherapies like Taxol or doxorubicin. The outcome for these cancers is poor, resulting in around 11,500 deaths annually in the UK. It is therefore important that we improve tumour response to chemotherapeutic drugs.

Chemotherapy kills cancer cells by inducing apoptosis, a form of programmed cell death that is regulated by the Bcl-2 family of proteins. Patient response to chemotherapy correlates with the sensitivity of their cancer cells to apoptosis, which is determined by the interactions between the Bcl-2 proteins on mitochondria. These interactions are therefore central to understanding whether or not a cancer cell will die in response to a chemotherapeutic drug. This key role of Bcl-2 proteins as a nexus for cancer cell death has led to recent introduction of drugs such as venetoclax, which directly target these interactions. However, heterogeneity in the apoptotic response results in incomplete killing of cancer cells and thus contributes to acquired resistance. Understanding how apoptotic heterogeneity is established can therefore identify strategies by which the response of cancer cells to chemotherapeutics can be improved.

We have established a proximity biotin labelling/mass-spectrometry approach to identify the interactome for Bcl-2 family proteins in BC cells. This approach has identified several novel interacting proteins that regulate Bcl-2 protein function and establish the threshold for apoptosis. This project will use this approach to define the Bcl-2 protein interactome in different therapy resistant BC cells, identify key Bcl-2 family regulatory interactions, and validate potential targets for sensitising BC cells to chemotherapeutics using 3D-organoid models.

Entry Requirements:
Candidates must hold, or be about to obtain, a minimum upper second class (or equivalent) undergraduate degree in a relevant subject. A related master’s degree would be an advantage. Applications from all nationalities are welcome.

Funding Notes

The Studentship will cover an annual stipend (currently at £19,000 per annum), running expenses and PhD tuition fees at UK/EU rates. Where international student fees are payable, please provide evidence within your application of how the shortfall will be covered (approximately £19,000 per annum).

The length of this project will be FOUR YEARS.

Related Subjects

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