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, has been 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.

What does this research aim to achieve?

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. 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.

Dr Fletcher and her team aim 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.

This Idea project will look to study replication stress in chondrosarcoma cells and, taking this a step further, investigate what happens when the oxygenase is blocked.

How could this project improve treatment options for chondrosarcoma patients?

Little is understood about the genetic and metabolic changes which lead to chondrosarcoma. By taking steps to further this understanding, this research has the potential to pave the way for vital new treatment strategies.

The knowledge gained from this project will allow researchers to more closely model the genetic, therapeutic, and environmental contexts needed to effectively target and eradicate chondrosarcoma cells.

Furthermore, by applying these findings to test novel combinations of targeted drugs in the laboratory setting, this research has the potential for translation to the clinical setting, providing a direct line of sight to future patient benefit.

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