Researchers at the Royal Orthopaedic Hospital (ROH) have helped make an important breakthrough that could lead to ‘kinder’ treatments for children with bone cancer, and save lives.
The research, which was led by Dr Darrell Green, from University of East Anglia’s (UEA) Norwich Medical School and Dr Katie Finegan from the University of Manchester, identifies a set of key genes that drive bone cancer spread to the lungs in patients. In further experiments in mice with engineered human bone cancer cells that lack these key genes, the cancer cannot spread to the lungs.
Current treatment can be very hard on children and features a mixture of chemotherapy and limb amputation and still, the five-year survival rate is at just 42 per cent – largely because of how rapidly bone cancer spreads to the lungs.
This important study was delivered by ROH’s Research and Development team between 2017 and 2020. As the only NHS Trust involved in the project, the ROH Research Tissue Bank contributed all of the essential clinical samples and data for 50 osteosarcoma patients which provided cell line model for this research. Their research nurses undertook the consenting of all participants and the collection, preparation and submission of their anonymised clinical samples and clinical data to Dr Green in line with patient consent and ethical committee approvals.
According to Public Health England (PHE), there is an average of 162 new cases of osteosarcoma per year in the UK. As one of just five Sarcoma Specialist Centres, ROH sees a significant proportion of the UK’s rare osteosarcoma referrals. Therefore achieving the recruitment target of 50 participants in this short space of time could only have been achieved through the ROH’s unique patient population and its well-established research tissue bank infrastructure, which is kindly supported by the Bone Cancer Research Trust (BCRT).
The genetic drivers that cause osteosarcoma are well known (TP53 and RB1 structural variants) but much less is known about what drives its spread to other parts of the body.
Dr Green said: “Because primary bone cancer spreads so fast to other parts of the body, it’s very important to solve exactly why this happens.
“We developed new technology to isolate circulating tumour cells in the blood of patients. These cells are critical for scientific study because they effectively carry out the metastatic process. This was extremely challenging because there is only one such cell per billion normal blood cells – it took over a year to develop but we cracked it.
“It was also challenging because most studies investigating circulating tumour cells are performed in common adult cancers where the methods significantly differ because the cancer biology is so different.
“Osteosarcoma is a less common sarcoma cancer so we had to start from scratch to not only find these cells in the first place, but to keep them alive so we could profile their gene expression.”
After profiling tumours, circulating tumour cells (CTCs) and metastatic tumours from patient donors, they were able to identify a potential driver for metastasis – known as MMP9.
Dr Green said: “This driver that we identified is well known in cancer, but it is also considered ‘un-druggable’ because the cancer quickly becomes resistant to treatment, or it finds a way to escape being targeted.
“So we thought we would try something a bit clever and find the ‘master regulator’ of MMP9 so that we could ‘action’ the ‘un-actionable’.”
The team began collaborating with researchers at the University of Manchester who were working on the proposed master regulator of MMP9 - MAPK7 - in several cancers using mouse models including osteosarcoma.
Together, they engineered human osteosarcoma cells to contain a silenced version of MAPK7. They found that when these cells were put into mice, the primary tumour grew much more slowly. Importantly, it didn’t spread to the lungs – even when the tumours were left to grow for a long time.
“This is really important because not only do we now have a gene pathway associated with metastasis, we know that removing this gene pathway actually stops cancer spread in a live animal. And we also know how and why this is happening - through hijacking the immune system.
“The next step already gearing up to take place is to silence this pathway in treatment form, now that we have shown how critical this pathway is.
“If these findings are effective in clinical trials, it would no doubt save lives and improve quality of life because the treatment should be much kinder, compared to the gruelling chemotherapy and life changing limb amputation that patients receive today.”
Senior author Dr Katherine Finegan from the University of Manchester said: “It has been great to work together with Darrell and the team at UEA. This is the first output from a new co-operative we have set up to tackle the significant unmet need that is finding an effective treatment once osteosarcoma has spread. This co-operative called OMeNet brings together researchers from across the UK to cohesively study the spread of osteosarcoma and expedite the discovery of new treatments.
“Using Darrell’s genetic insights from patient material, we were able to validate their work in models of primary bone cancer. As a result, we have highlighted a potential new way to treat metastatic bone cancer by targeting a key protein that promotes metastases: MAPK7. This work has uncovered a novel treatment option for osteosarcoma, something we have not had for the last 40 years.
“In the Finegan lab we are already in the process of developing new drugs against MAPK7, which we hope to implement for the benefit of primary bone cancer patients in the future.
“We would also like to thank the charity Friends of Rosie who funded the work in the Manchester lab and support childhood cancer research here in the North West.”
The research was led by UEA in collaboration with the University of Manchester, the Earlham Institute, the Royal Orthopaedic Hospital in Birmingham, the Royal Papworth Hospital in Cambridge, Epistem Limited, the University of Sydney, the Norfolk and Norwich University Hospital.
You can read the full research article here.
