University of East Anglia Featured PhD Programmes
Sheffield Hallam University Featured PhD Programmes
Lancaster University Featured PhD Programmes

Functional characterisation of novel cGAS/STING mediated immune activating agents for rationalised combination therapy in breast cancer.

This project is no longer listed on FindAPhD.com and may not be available.

Click here to search FindAPhD.com for PhD studentship opportunities
  • Full or part time
    Mr S McIntosh
    Dr K Savage
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (UK Students Only)
    Funded PhD Project (UK Students Only)

Project Description

A significant proportion of breast cancers exhibit a DNA double strand break repair (DSBR) deficiency and are genomically unstable. Evidence suggests that genomic instability correlates with response to immune checkpoint inhibition. This has been attributed to accumulation of mutations resulting in neo-antigen expression, leading to an immune response, which is inhibited by immune checkpointing proteins such as PD-L1. However, we recently reported an additional mechanism for immune activation in DSBR-deficient breast cancers. We reported that cytoplasmic DNA resulting from defective DNA repair triggers the cGAS/STING pathway, causing IRF3 activation and switching on an immune transcriptional cascade. Furthermore, we have developed and validated a gene expression signature termed the DNA Damage Immune Response (DDIR) assay that identifies a subset of breast cancer patients with activation of this immune transcriptional cascade. The signature has been validated in several independent datasets, including our recent prospective Neo-DDRD clinical trial. Additionally, we have found that this signature is “switched on” in response to DNA damage, suggesting that therapeutic challenge with DNA-damaging chemotherapies may sensitise tumours to immune checkpoint blockade.

Our data suggests that loss of homologous recombination and/or inability to resolve RNA/DNA hybrids (R-loops) in cells lacking key components of the FA/BRCA machinery, along with an accumulation of cytoplasmic DNA following DNA damage, can activate the DDRD-immune response. We have also shown that treatment with DNA-damaging drugs can activate the DDRD-immune response.

We have carried out a screen of FDA approved drugs to identify novel compounds and pathway that can activate this pathway with the goal of repurposing these drugs for immune activation and combination therapies with immune checkpoint blockade.

This project will focus on validating a small selection of the hits form this screen and characterising the role of these drugs and their target pathways in cGAS/STING activation. We will also use a number of different pre-clinical model systems to assess the combination of these drugs with immune checkpoint blockade, to identify rational combination therapies for breast cancer.

ENTRY REQUIREMENTS

Candidates should have or expect to obtain a 2:1 or higher Honours degree or equivalent in a relevant biomedical or life sciences subject.

Funding Notes

*FUNDING CONFIRMED – Julie Loughery Studentship*

Eligibility for fees (£4,327 for 2019/20, 2020/21 TBC)

When applying, please choose 'MEDICINE' as your subject area/School.

References

Please visit the School of Medicine, Dentistry and Biomedical Sciences, Centre for Cancer Research and Cell Biology, website for further details about the Centre:

http://www.qub.ac.uk/research-centres/CentreforCancerResearchCellBiology/

When applying, please choose 'MEDICINE' as your subject area/School.



FindAPhD. Copyright 2005-2020
All rights reserved.