Recent research from Barts Cancer Institute (BCI) at Queen Mary University of London has identified a novel therapeutic strategy to target lung cancer tumours that lack the gene LIMD1. The proof-of-concept study, published in Cell Death and Disease, could pave the way for the development of vital new treatment options for this cancer type of unmet need.

We spoke with Professor Tyson V Sharp from BCI’s Centre for Cancer Cell & Molecular Biology, who led the study with Dr Sarah Martin, to find out more about the research and the significance of the findings.

What is the new study about?

Our new study focuses on a specific subtype of lung cancer where there is a loss of the tumour suppressor gene LIMD1. Our previous work has shown that loss of LIMD1 is key to initiating and driving lung cancer progression.

My research group has defined and studied this lung cancer subtype and its unique biology for over 17 years. Through our understanding, we estimate that about 20,000 lung cancer patients each year in the UK (1.2 million worldwide) are diagnosed with this subtype of lung cancer. Unfortunately, there are currently no specific targeted therapies for those patients with LIMD1-deficient tumours.

This seminal investigation and publication set out to determine whether it is possible to target and kill LIMD1-deficient cancer cells and thus potentially extend, and even save, the lives of this huge cancer patient population.

What were the findings from the study?

Our study identified a drug, called PF-477736, which selectively kills LIMD1-deficient cancer cells in many cellular contexts, including in vivo models where it significantly inhibited growth of human lung tumour cells. Interestingly, we observed that killing of the cancer cells occurred via a surprising ‘off-target’ mechanism that requires inhibition of multiple pathways. This is perhaps key to targeting loss of key tumour suppressors like LIMD1.

Why are these findings important?

These finding are important because it now means we can pursue this therapeutic approach and develop better drugs that are even more selective and less toxic than the PF-477736 drug tool, which we hope could eventually be translated into clinical trials.

In addition to lung cancer, LIMD1 is also lost in breast, renal, cervical and head and neck cancers, and possibly many more epithelial-cell derived cancers. Therefore, using the methodology and the findings discussed in our new paper, it may be possible to develop new targeted therapies for many different cancer types that have LIMD1 deficiency. We hope this could make a profound difference in treating cancer subtypes of significant unmet clinical need.

What are the next steps for this research?

We are now expanding the study to obtain more pre-clinical data on the efficacy of LIMD1 targeted treatments in experimental models of lung cancer. We are also examining how drugs that target and kill cancer cells in the same way as PF-477736 could be used in combination with immunotherapies to improve treatment efficacy.

This research was supported by funding from the Medical Research Council, Barts Charity, Pfizer and Cancer Research UK.

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More information

• Research paper: Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes. Cell Death Dis 12, 1075 (2021). https://doi.org/10.1038/s41419-021-04355-7
• Find out more about the research in Professor Sharp’s laboratory
• Find out more about the lung cancer research at BCI