Victoria Tippett, Professor Ali Gartland and Professor Dominique Heymann  

University of Sheffield 

Part funded PhD project (2019-2023)

BACKGROUND TO THE RESEARCH PROJECT

Current treatment for osteosarcoma relies on classical chemotherapy drugs which have significant side effects due to the fact that they also kill non-cancerous cells.  Patients also often become resistant to the therapy which means that it no longer works, further limiting their treatment options. 

This project aimed to find new, kinder drugs that will work in osteosarcoma, even when they become resistant to the first line therapy. The objective of this study was to use High Throughput Screening (HTS) to identify drug candidates effective against osteosarcoma.

KEY RESULTS

The Gartland lab has tested 4,320 compounds from a “drug library”, which includes many drugs and natural compounds that have already been shown to be harmless in people, for their effect at reducing the growth of osteosarcoma cells. Their extensive investigations using osteosarcoma cell lines in the laboratory have identified 5 compounds that are highly potent, requiring low doses to reduce osteosarcoma cell growth. These drugs also reduced the ability of the osteosarcoma cells to move, suggesting they may be able to prevent osteosarcoma spreading (metastasising) to other parts of the body. 

The team also tested these drugs against osteosarcoma cells that they had made resistant to conventional doxorubicin chemotherapy and they were able to kill these cells too. In addition to these findings specifically in osteosarcoma, these drugs have been shown to have effects in other cancers. 

They are now trying to get more evidence that these new drugs work so we can take them forward to being used in patients. The Gartland lab also used the chemoresistant cells they developed to investigate the way in which the osteosarcoma cells stop responding to the first line chemotherapy. Excitingly they have found new signalling pathways and potential drug targets that are involved in the cells becoming chemoresistant and now want to investigate these further as potential new treatment options for osteosarcoma. 

OTHER OUTPUTS, KNOWLEDGE AND FUTURE STEPS

Publications:

V.L. Tippett, L. Tattersall, K.M. Shah, Ab Latif, N.B, M.A. Lawson, A. Gartland. “The strategy and clinical relevance of in vitro models of MAP resistance in osteosarcoma: a systematic review” Oncogene 2022 https://doi.org/10.1038/s41388-022-02529-x