As chondrosarcomas are resistant to chemotherapy and radiotherapy, surgery is the mainstay of treatment. Further therapeutic options for patients whose cancer progresses remain very limited. A greater understanding of the genetic changes underlying chondrosarcoma is urgently required to guide the development of much-needed targeted treatments.

Chondrosarcomas are often characterised by a mutation in the gene which codes for a family of enzymes (proteins) called the ‘Isocitrate dehydrogenases’ (IDH). However, there are significant gaps in our knowledge as to how and why this leads to cancerous change.

Dr Sally Fletcher, working with Prof Mathew Coleman at the University of Birmingham, was awarded an Idea Grant by Bone Cancer Research Trust to explore whether the disturbances caused by this genetic mutation can be harnessed as a potential target for the treatment of chondrosarcoma.

Aims and results of the project?

During the process of normal cell division, a cell’s DNA is replicated. When DNA replication malfunctions, the genetic information it contains becomes unstable. This is a major known driver of cancerous change. However, this so-called ‘replication stress’ has not been specifically explored in chondrosarcoma. By investigating replication stress, the team hoped to find out more about how chondrosarcoma develops, and how it progresses to a more aggressive disease.

As such, researchers are uncertain as to whether there is an association between IDH mutation, replication stress and genetic instability (an increased tendency for mutations) in chondrosarcoma.

Dr Fletcher’s research group has expertise in another group of proteins, the oxygenase enzymes, whose activity can be hindered by changes to cellular processes caused by mutated IDH enzymes. Blocking or ‘inhibiting’ one particular oxygenase was found to cause replication stress in cell lines grown in the lab.

The team aimed to assess whether a reduction in oxygenase activity could play a crucial role in the development and progression of chondrosarcoma and, as such, represent a crucial target for treatment. By looking at replication stress in chondrosarcoma cells, they aimed to investigate what happens when the oxygenase is blocked.

They found that chondrosarcoma cells were sensitive to drugs that block oxygenase in laboratory models. Although at a very early stage, these findings suggest that these drugs are worth further investigating for their potential use in treating chondrosarcomas.

Chondrosarcoma can be difficult for scientists to study because it is hard to accurately recreate the environment inside the body. In future research the team plan to develop new 3D chondrosarcoma cell models to study chondrosarcoma in the laboratory under conditions that more accurately resemble those found in the body. These models could be used to test potential treatments, which will lead to patient benefit in the future.

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