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Gene study broadens bone cancer treatment options

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UK researchers have made an important breakthrough that could lead to ‘kinder’ treatments for children with bone cancer and save lives.

New research has identified a set of key genes that drive the spread of bone cancer to the lungs – and uncovered a new treatment option for osteosarcoma, one of the most common types of bone cancer.

The researchers from the University of East Anglia and University of Manchester believe the research has led to one of the most important discoveries in the field for more than 40 years.

Current treatment for osteosarcoma is gruelling, and can include chemotherapy and limb amputation; while the five-year survival rate remains poor at just 42 per cent. This is largely due to how rapidly bone cancer spreads 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 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. These figures have remained stagnant, with no significant breakthroughs in treatment, for more than four decades.”

The genetic drivers that cause osteosarcoma are well known 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.

“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, the researchers were able to identify a potential driver for metastasis, known as the MMP9 gene.

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’.”

UEA researchers collaborated with the University of Manchester who were working on the proposed master regulator, known as MMP9-MAPK7, in several cancers using mouse models.

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 significantly slower and also did not spread to the lungs.

“Getting even deeper, our study shows that silencing the MAPK7 gene prevented 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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