New target identified for drugs to treat cancer and age-related diseases

The research, published in Nature Cell Biology and led by the Laboratory of Medical Sciences (MRC-LMS), identifies a new target for a class of drugs that selectively eliminate cells that are known to provoke inflammation.

The drugs, known as senolytics, eliminate senescent ’zombie‘ cells that have stopped multiplying in response to either cell damage or ageing. Although senescent cells are inactive, they continue to release proteins that can induce inflammation in the body. Normally the body eliminates senescent cells through the immune system. However, ageing and disease can disrupt this process. Consequently, these cells can accumulate in the body, causing chronic inflammation and tissue disruption.

This further fuels the ageing process and disease development, which in turn generates more senescent cells, forming a vicious cycle.

By removing senescent cells, senolytics reestablish tissue stability, improving the outcome of many age-related diseases.

Though pre-clinical studies have shown some promising results, there are currently no senolytics on the market and those in clinical trials have limitations, creating calls for more effective options to be developed.

Lead author, Professor Jesus Gil (Head of the Senescence Research Group at LMS), said: “In a previous study we showed the potential of repurposing existing drugs, but there are only limited drugs to choose from.

“In this study, we greatly expanded our selection pool by seeking targets in over 7,000 ‘druggable’ genes. We were thrilled to reveal previously unknown vulnerabilities of senescent cells. This opens up new possibilities for treating age-related diseases.”

The team used an approach called RNA interference (RNAi) to assess the molecular pathways influencing the survival of senescent cells. RNAi prevents protein production by reducing gene expression.

They screened RNAi molecules targeting over 7,000 genes and selected the RNAi molecules that selectively killed senescent cells, but not normal cells.

As a result, they identified a senolytic target pathway called coat protein complex I (COPI). Inhibiting this pathway, which is responsible for carrying proteins in the cells, led to the death of senescent cells.

They also showed that targeting this pathway improved outcomes in mouse models of cancer and fibrosis.

Co-author, Professor J.P. Martinez-Barbera (UCL Great Ormond Street Institute of Child Health), said: “When we tested these senolytics in preclinical models of a paediatric brain tumour called craniopharyngioma, we were amazed to see that the majority of the senescent cells had been killed.

“These results have encouraged us to explore these drugs further as potential treatments against these aggressive tumours.”

Building on these findings, the researchers explored drug candidates that target the COPI pathway. Although there are some existing drugs that directly interfere with the COPI pathway, they have limited effectiveness because they only have a short lifespan in the bloodstream, so were not considered suitable for clinical use.

The LMS team collaborated with Professor Edward Tate at Imperial College London and Myricx Bio, an Imperial spin-off, to investigate whether a different class of drugs which indirectly inhibit the COPI pathway, N-myristoyltransferase inhibitors (NMTi), could also target senescent cells. The results were positive-  NMTi demonstrated potent senolytic effects, effectively improving the outcome of cancer and fibrosis in mouse models.

Lead author Professor Jesus Gil said: “This work defines a novel class of senolytic drugs that expand the possibilities to treat a wide range of diseases associated with senescence including cancer, idiopathic pulmonary fibrosis (IPF) or non-alcoholic steatohepatitis (NASH).”

The study opens up a new avenue of opportunity to develop drugs which can attack major diseases such as cancer, fibrosis, and other ageing-related conditions. The team is now looking ahead to further research and potential clinical trials, representing a promising advancement in the quest for healthier ageing.

The research was a collaborative effort between LMS, Imperial College London, UCL, The Institute for Research in Biomedicine from Barcelona, University of Southampton and The Francis Crick Institute.

Myricx Bio, an Imperial spin-off, provided access to the NMTi used in the study. UKRI and CRUK were the main funders of this study.

Links

• Research in Nature Cell Biology
• Professor J.P. Martinez-Barbera's academic profile
• UCL Great Ormond Street Institute of Child Health
• UCL Population Health Sciences

Image

• Credit: Murat Photo on iStock

Media contact 

Poppy Danby 

E: p.danby [at] ucl.ac.uk