Sutherland Lab

Alternations in the KEAP1-NRF2 pathway are found in a high percentage of non-small cell lung cancers and led to enhanced NRF2 activity. Critically, increased expression of NRF2 is associated with poor prognosis, highlighting the urgent need for new therapeutic strategies for this subgroup of patients.

To understand the effect of KEAP1-NRF2 pathway alternations on lung cancer, we have engineered in vivo models that faithfully mimic KEAP1-mutant human lung cancers.

Current work is focused on identifying effective treatments that target KEAP1-mutant lung cancer. To achieve this, we will utilise CRISPR/Cas9 technologies and perform high-throughput drug screening in collaboration with the National Drug Discovery Centre (NDDC).

Immunotherapeutic approaches, such as monoclonal antibodies targeting PD-1/PD-L1 and CTLA-4 unleash the T cell response to eliminate tumour cells. While this approach has shown considerable promise in lung cancer patients, not all patients will respond to conventional T cell-based immunotherapies.

In response to this, we aim to harness the anti-tumour activity of other immune cell populations, such as Natural Killer cells and macrophages.

Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, with a five-year survival rate of less than 7 per cent. Critically, SCLC has a high propensity for early spread, with 50-80 per cent of patients harbouring metastatic lesions in multiple organs at the time of diagnosis.

To understand underlying mechanisms controlling metastatic dissemination, we have developed in vivo SCLC models to augment metastatic activity.

We aim to identify novel therapeutic approaches to restrict primary and metastatic disease in SCLC.

Emerging evidence suggests that small cell lung cancer (SCLC) is a heterogeneous disease that can be classified into four distinct subtypes based on the differential expression of the transcription factors ASCL1, NEUROD1, POU2F3 and YAP1. This raises interesting biological questions that could directly inform the therapeutic treatment of SCLC patients.

We aim to develop sophisticated CRISPR/Cas9 in vivo models to explore the genetic and cellular drivers of heterogeneity.