Osteosarcoma is the second most common form of primary bone cancer, yet few advances in treatment strategies have been made over the last 25 years.

Background of the research:

Although chemotherapy has enhanced the survival of Osteosarcoma patients, few advances have been made in the last 25 years. This is largely due to the poor understanding of the genetic alterations involved in the development of the disease.

Over the past 10 years or so, advances have been made in gene screening technology that allows the genetics of a disease to be investigated. This is a relatively high through-put technique and is used to gain a better understanding of the specific genes, or mutations, that are involved in disease initiation and progression.

The project aimed to identify genes that when silenced would result on the death of osteosarcoma tumour cells. Drug molecules that inactivate the proteins associated with these genes, were then considered as potential treatments.

Results of the study:

An example of those genes is FGFR1. The research team confirmed that osteosarcoma cells were sensitive to drugs which stopped the function of the FGFR1 protein, especially those cells that had increased copies of the FGFR1 gene. This result highlighted the potential of using drug molecules FGFR1 inhibitors to treat patients with osteosarcoma that have increased levels of the FGFR1 gene.

Another gene named Retinoblastoma 1 gene (RB1) is frequently mutated in osteosarcoma tumour samples. Osteosarcoma tumour cells that had a mutation of RB1 were found to be especially dependent on another gene named DYRK1A, and a chemical inactivator of the DYRK1A protein was found to increase cell death in osteosarcoma cells. This result paved the way for further work, to see if drugs that inhibit the DYRK1A protein may be considered as potential treatments for OS patients.

PARP is a protein that helps cells repair themselves if they become damaged, by for example chemotherapy. PARP inhibitors stop PARP from repairing the damage, resulting in the death of tumour cells. PARP inhibitors, in combination with other chemotherapeutics, have shown promise in treating some tumours (e.g. breast cancer). The results indicated that many OS tumour cells where not profoundly sensitive to PARP inhibition; however, suggested a role in a subset of patients and further investigation in this area is warranted.

In conclusion, the results supported the pre-clinical identification and validation of several druggable therapeutic targets to facilitate development into clinical trials.

The Bone Cancer Research Team caught up with Dr Harriet Holme at the 2017 British Sarcoma Group Conference as she presented her research findings to those attending. Read more about the British Sarcoma Group Conference and the updates we heard from Dr Holme in our news piece here.

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