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ARM Innovation Hub
13 July, 2020 - 16:31 By Tony Quested

Genetic key to fighting devastating bone cancer in children

Researchers at the Universities of East Anglia and Manchester have made a breakthrough that could lead to kinder treatments for children with bone cancer – and save lives.

Current treatment is gruelling with outdated chemotherapy cocktails and even limb amputation. Even then, the five-year survival rate is poor at just 42 per cent – largely because of how rapidly bone cancer spreads to the lungs.

New research 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.  

The research was led by Dr Darrell Green, from UEA’s Norwich Medical School and Dr Katie Finegan from the University of Manchester. 

Dr Green was inspired to study childhood bone cancer after his best friend died from the disease as a teenager. Now the team has made what could be the most important discovery in the field for more than 40 years.

He said: “Primary bone cancer is a type of cancer that begins in the bones. It’s the third most common solid childhood cancer, after brain and kidney, with around 52,000 new cases every year worldwide.

“It can rapidly spread to other parts of the body, and this is the most problematic aspect of this type of cancer. Once the cancer has spread it is very difficult to treat.

“Around a quarter of patients have cancer that has already spread by the time they are diagnosed. Around half of patients with apparent localised disease relapse, with cancer spread detected later on. These figures have remained stagnant, with no significant breakthroughs in treatment, for more than four decades.

“In high school, my best friend Ben Morley became ill with primary bone cancer. His illness inspired me to do something about it myself because during my studies I realised that this cancer has been all but left behind others in terms of research and treatment progress. So I studied and went through university and obtained my PhD to eventually work in primary bone cancer.

“I want to understand the underlying biology of cancer spread so that we can intervene at the clinical level and develop new treatments so that patients won’t have to go through the things my friend Ben went through. Ultimately we want to save lives and reduce the amount of disability caused by surgery.”

The research team investigated the most common type of primary bone cancer called osteosarcoma.

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.

“Getting even deeper, our study shows that silencing MAPK7 stopped metastasis because that gene pathway was hijacking a particular part of the immune system that caused the spread,” said Dr Green.

“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.”

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