Luke Tattersall, Professor Ali Gartland and Professor Dominique Heymann

University of Sheffield 

Fully funded postdoctoral position (2019-2023)

BACKGROUND TO THE RESEARCH PROJECT

Osteosarcoma is the most common type of primary bone cancer affecting children and adolescents, and it is a rare and often fatal disease. Historically, the overall 5-year survival rates for osteosarcoma are dire at below 20% with surgical intervention alone. The introduction of the addition of chemotherapy treatment after surgery in the 1970s radically increased rates to 50%. Since then, and with the introduction of chemotherapy before surgery, the survival rate further increased to 60%. However, there have been no real advances in treatment options and survival rates have remained poor. The 5-year survival rate is reported to be 53% for patients under 40, versus 22 % for those above. The rate is even worse for patients who present with metastatic disease at less than 30% and this has actually declined every decade, with no significant change in the survival rate when comparing current figures with those from the 1970s. 

Current treatments for osteosarcoma are also brutal and rely 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.

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:

The Gartland lab is currently refraining from publishing the results from the studies of Dr Luke Tattersall until successful IP has been filed and protected for the drug compounds, in order to increase translatability into patients. The lab is trying to further validate the hits from the screening to get the pre-clinical evidence to take the hits forward to clinical use in patients. They are also trying to modify the drugs to target them specifically to bone and so reduce any potential side effects.

Presentations:

Oral Presentation at the first HWWP research symposium, London, UK, “Can we find new effective treatments for osteosarcoma?” L. Tattersall, V.L Tippett, A. Higginbottom, A.Gartland 

Poster Presentation at the Bone Research Society Annual Meeting, Liverpool, UK, “Establishment and characterisation of a human osteosarcoma metastatic cell line derived from a patient’s lung for future preclinical use” L. Tattersall, V.L Tippett, J.K. Rantala, A. Higginbottom, A.Gartland 

Snap Oral Presentation at the 12th Annual Mellanby Centre Research day, Sheffield UK, “Establishment and characterisation of a human osteosarcoma metastatic cell line derived from a patient’s lung for future preclinical use” L. Tattersall, V.L Tippett, J.K. Rantala, A. Higginbottom, A.Gartland 

Oral Presentation at the first PRESTO meeting, Ferrara, Italy. “The P2RX7B splice variant modulates osteosarcoma cell behaviour and metastatic properties” L. Tattersall, K.M. Shah, D.L. Lath, A. Singh, J.M. Down, E. De Marchi, A.Williamson, F.Di.Virgilio, D. Heymann, E.Adinolfi, W.D. Fraser, D. Green, M.A. Lawson A.Gartland 

Oral Presentation at the Bone Cancer Research Trust Annual Conference (North) Leeds UK. “Can we find new effective treatments for osteosarcoma?” L. Tattersall, V.L Tippett, A. Higginbottom, A.Gartland 

Snap Oral Presentation at the 11th Annual Mellanby Centre Research day, Sheffield UK, “Can we find new effective treatments for osteosarcoma?” L. Tattersall, V.L Tippett, A. Higginbottom, A.Gartland 

Poster Presentation at the BSG annual conference Liverpool UK, “Can we find new effective treatments for osteosarcoma?” L. Tattersall, V.L Tippett, A. Higginbottom, A.Gartland 

Oral Presentation at the 10 year UK Purine club anniversary conference, Sheffield UK, P2X7RB increases ectopic bone disease and lung metastasis in vivo L. Tattersall, K.M. Shah, D. Lath, J. Down, E. De Marchi, A. Williamson, F. Di Virgilio, E. Adinolfi, M.A. Lawson, A. Gartland. 

Oral Presentation at the 9th Annual Mellanby Centre Research day, Sheffield UK, Effects of P2X7RB expression on MNNG-HOS osteosarcoma cells in vitro L. Tattersall, E. De Marchi, A. Williamson, F. Di Virgilio, M.A. Lawson, E. Adinolfi, A. Gartland 

Poster Presentation at the BACR tumour microenvironment meeting, Nottingham UK P2X7RB increases ectopic bone disease and lung metastasis in vivo in osteosarcoma Tattersall. L, Down. J, Lath. D, De Marchi. E, Williamson. A, Di Virgilio. F, Adinolfi. E, Lawson. M.A, Gartland. A