Alex Dzhoneva, Professor Katie Finegan, Professor Kaye Williams, Dr Adam McMahon

University of Manchester 

Part funded PhD project (2019-2023)

BACKGROUND TO THE RESEARCH PROJECT

There was evidence from recent previous research work undertaken in this lab that a protein called ERK5 could promote the progression of osteosarcoma. Clinical studies have also revealed a strong link between ERK5 signalling and outcomes for osteosarcoma patients.  A recent study of samples from osteosarcoma patients showed that high levels of ERK5 correlated with disease progression (87% of patients), resistance to chemotherapy (53% of patients), and was detected in 70% of metastases, where it correlated with decreased overall survival.  

ERK5 is a protein and sends many messages to other proteins, which then tell the cell what to do. Cells responding to the signal are not only tumour cells, but also cells that belong to the body’s immune system, which in cancer, are hijacked to aid cancer progression. We have initial evidence that removing ERK5 interrupts the signals or “conversation” between the immune cells and the tumour cells. A tumour cells “conversation” with the immune system is essential for both tumour growth and spread to other parts of the body. When genetic approaches to remove ERK5 from osteosarcoma cells growing in mice are used, this stops spread of the osteosarcoma cells to the lung.  However, although we know that eliminating ERK5 from the cells has significant impact on osteosarcoma progression, we do not know exactly how this happens. Understanding the “how” is pivotal to understanding the best way to target this pathway and inform design of drugs acting against ERK5 signalling for future patient use. 

KEY RESULTS

• Blocking ERK5 either by the Finegan lab’s genetic approach or by their new patented drug stops osteosarcoma cells from being able to spread.

• Blocking ERK5 (drug/genetic approach) enabled the lab to use a lower dose of chemotherapy to get the same effect. This means, in the future, the drug could be used to lower chemotherapy doses and therefore enable kinder treatment plans for patients.

• Blocking ERK5 (drug/genetic approach) is a possible new immunotherapy for osteosarcoma. The Finegan lab found that their drug can make the immune system more able to attack osteosarcoma tumours and also that it may be able to make current on-the-shelf immunotherapy more effective.

• The Finegan lab analysed patient tumour samples and this suggested that we can use ERK5 levels in patient samples as a way to identify patients that might be at higher risk of their cancer spreading. 

• They have also found that most osteosarcoma patients tumours (~80%), but especially those patients tumours whose osteosarcoma had spread or had gone on to spread, had high ERK5 in them.  Due to having lots of ERK5, these 80% of osteosarcoma patients would be very likely to benefit from our drugs that block ERK5.

OUTPUTS 

This project has allowed the lab to secure onward funding from Sarcoma UK and LifeARc to progress their drugs further towards use in patients and to develop their work on ERK5 levels in patient tumours. This means that they can use this clinically to identify high risk patients early on and therefore offer the best opportunities for treatment.