Targeting the ‘Worst of the Worst’ – developing novel treatments for Poor Outcome Triple Negative Breast Cancers.

We will investigate biology driving the aggressive features of Poor Outcome Triple Negative Breast Cancers (PO-TNBCs). PO-TNBCs possess the worst outcomes amongst all breast cancers, with high rates of metastases and chemoresistance. Identifying genes/pathways involved will advance the development of targeted therapies to improve the survival of PO-TNBC patients. 

Triple Negative Breast Cancers (TNBCs) are characterised by high rates of metastases, relapses and chemoresistance. ‘Poor Outcome’ TNBCs (PO-TNBCs) represent the ‘worst subgroup of the worst subtype’. We will use new and existing knowledge to better target the metastasis and chemoresistance of PO-TNBCs. PO-TNBCs show hyperactivation of TGFβ signalling (TGFβ2, GLI2, Survivin, Slug) combined with loss of epithelial ΔNp63α/β function. These phenotypes are exacerbated by hyperactive SRC/AKT signalling, generating an oncogenic signalling loop. 

Aims and Objectives:  

1 Investigating how aberrant TGFβ-p63 biology contributes to PO-TNBC pathogenesis;  

2 Targeting PO-TNBC vulnerabilities to develop novel therapies;  

3 In vivo modelling of PO-TNBCs – testing of targeting strategies 

TNBCs are notoriously hard to treat, with no targeted therapies available. They are also very heterogenous, making it likely that multiple different pathways are involved. We will model PO-TNBCs in vitro using a range of standard (qPCR/immunoblotting/co-IPs), and more specialised (ChIP-seq/RNA-seq) laboratory techniques in order to identify pathways key to PO-TNBC behaviour. We will test PO-TNBC dependencies/vulnerabilities and source inhibitors which counteract this biology. Finally, we will in vivo model PO-TNBCs, to evaluate if the vulnerabilities we have identified represent the basis of a novel therapy approach to improve PO-TNBC patient survival. 

Start Date: October 2022